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Oxygen debt in critically ill patients

Monitoring and additionals

Paul A. van Beest

ISBN : 978-90-367-5782-9

Printed by :

The research described in this thesis was performed within the departments of Intensive Care,

Cardiology and Anaesthesiology of

Academic Medical Center, Amsterdam

Gelre Hospitals, location Lucas, Apeldoorn

Martini Hospital, Groningen

Medical Center Leeuwarden

University Medical Center Groningen

© 2012 by P.A. van Beest.

No part of this book may be reproduced in any form without permission from the author.

RIJKSUNIVERSITEIT GRONINGEN

Oxygen debt in critically ill patients

Monitoring and additionals

Proefschrift

ter verkrijging van het doctoraat in de

Medische Wetenschappen

aan de Rijksuniversiteit Groningen

op gezag van de

Rector Magnificus, dr. E. Sterken,

in het openbaar te verdedigen op

woensdag 21 november 2012

om 14.30 uur

door

Paul Alexander van Beest

geboren op 25 mei 1975

te Numansdorp

Promotor: Prof. dr. T.W.L. Scheeren

Copromotores: Dr. M.A. Kuiper

Dr. P.E. Spronk

Beoordelingscommissie: Prof. dr. J. Bakker

Prof. dr. W.F. Buhre

Prof. dr. M.M.R.F.Struys

Paranimfen Dr. Dedmer Schaafsma

Remco van Beest

Contents

Introduction 9 Chapter 1 The use of venous oxygen saturations as a goal: a yet unfinished 17

puzzle. A clinical review Addapted from Crit Care 2011, 15: 232

Chapter 2 The incidence of low venous oxygen saturation on admission in the 41

ICU: a multicenter observational study in the Netherlands Crit Care 2008, 12: R33 Chapter 3 Relation between mixed venous and central venous saturation in 57

sepsis: no influence of sepsis origin Crit Care 2010, 14: 219 Chapter 4 Femoral venous oxygen saturation is no surrogate for central venous 77

oxygen saturation Crit Care Med 2012, accepted

Chapter 5 Measurement of lactate in a prehospital setting is related to outcome 97 Eur J Emerg Med 2009, 16(6): 318-322

Chapter 6 Cumulative lactate in ICU patients: magnitude matters 113 2012 submitted Chapter 7 Veno-arterial PCO2 difference as a tool in resuscitation of septic 131

patients 2012 submitted

Chapter 8 Summary 147 Nederlandse samenvatting 158 Abbrevations 164 Publications (full papers) 168 Dankwoord 172

Introduction

Shock is defined as global tissue hypoxia secondary to an imbalance between

systemic oxygen delivery (DO2) and oxygen demand (VO2). Unrecognized and untreated

global tissue hypoxia increases morbidity and mortality. Accurate detection of global tissue

hypoxia is therefore of vital importance. Physical findings, vital signs, measuring central

venous pressure (CVP) and urinary output are important, but insufficient for accurate

detection of global tissue hypoxia [1-3]. Measurement of mixed venous oxygen saturation

(SvO2) from the pulmonary artery (PA) has been advocated as an indirect index of tissue

oxygenation [4]. However, as a result of an extensive debate in literature [5-7], the use of the

pulmonary artery catheter (PAC) has become, justifiable or not [8], somewhat unpopular. In

contrast, insertion of a central venous catheter in the superior vena cava via the jugular or

subclavian vein is considered standard care in critically ill patients. Just as SvO2, the

measurement of central venous oxygen saturation (ScvO2) has been advocated as a

derivative of global tissue hypoxia. Venous oxygen saturations have been subject of

research for over fifty years, but especially over the last decade the amount of literature

describing changes in ScvO2 and SvO2 in critically ill patients increased substantially.

The main reason for the revival of interest in venous oxygen saturations was the

publication of the so-called Early Goal-Directed Therapy (EGDT) study by Rivers et al [9]. In

this study an impressive mortality reduction was achieved in favour of the patients treated

according to the EGDT protocol which included ScvO2-guided therapy. This led to high

expectations with respect to the use of central venous oxygen saturation as a therapeutic

goal. In a strict sense the goal would be a ScvO2 value ≥70% which deems a lower ScvO2 at

patient presentation. After a literature search on the clinical use of venous oxygen

saturations in various settings, chapter 2 describes the occurrence of low ScvO2 and SvO2

values in 340 critically ill patients at intensive care unit (ICU) admittance. Central question: is

EGDT still commonly indicated as suggested by the Surviving Sepsis Campaign Guidelines

[10], if a minority of septic patients reveals low venous oxygen saturations?

The PAC, together with the defining variables it provides including SvO2, has been a

fundamental hemodynamic monitoring tool in ICUs for over 40 years. Consequently,

replacement of SvO2 by ScvO2 in diagnostic and therapeutic strategies asks not only for

arguments but also for nuance. In other words, are both values equal or interchangeable, in

septic shock especially, and is this clinically relevant? In chapter 3 the generally adopted

difference of 5% between SvO2 and ScvO2 is addressed [11-13], also paying attention to the

question on the use of both variables in patients with septic shock.

In clinical practice, when insertion of a central venous catheter in the superior vena

cava via the jugular or subclavian vein is impossible, the alternative central venous access is

the femoral vein. Unfortunately, monitoring ScvO2 is then out of the question. However, as

shown in a recent survey, femoral venous oxygen saturation (SfvO2) is used during the first

hours of treatment [14]. Femoral access is quick and relatively safe and potentially very

useful in the care of acutely ill patients, especially if SfvO2 would provide diagnostic

information in accordance with ScvO2. The question whether SfvO2 is such an attractive

alternative is addressed in chapter 4. In 3 different populations the statistical agreement is

described: stable cardiac outpatients, patients undergoing high-risk surgery, and critically ill

ICU patients.

Venous oxygen saturations are the best surrogates for global tissue hypoxia at this

point and when used appropriately they are both useful diagnostic tools and of prognostic

value. However, venous oxygen saturations do not have the exclusive right to these

entitlements, because lactate has to be considered too. This product of metabolism, i.e.

glycolysis, has been monitored in ICUs for many years. It is known that in anaerobic

conditions lactate concentrations increases. As a consequence hyperlactataemia may serve

as a marker for tissue hypoxia as well. But the pathophysiology of hyperlactataemia is

complex and the meaning of hyperlactataemia in critically ill patients remains under debate

[15,16]. This controversy includes the use of lactate as a marker of hypoxia [17].

Nevertheless, the prognostic value of lactate in this context has not been questioned as

extensively.

Clinical application of point-of-care measurements of arterial blood gas, glucose and

lactate has been spread over the years in the emergency department (ED), operating room

(OR) and ICU. With the introduction of hand held lactate metres it became possible to

measure lactate outside these facilities or even outside the hospital. In chapter 5, the results

are reported of a feasibility study on the use of such hand held metres in a prehospital

setting. We compared the prognostic value of lactate with the prognostic value of vital signs

in both shock and non-shock patients. This is relevant because if lactate would outperform

vital signs, in non-shock patients especially, then lactate could be added to the current

diagnostic pallet available to paramedics.

In a later stage, i.e. after ICU admittance, persistence of hyperlactataemia could be a

sign of on-going disease without apparent improvement. Hyperlactataemia is associated with

multiple organ dysfunction syndrome (MODS) [18-21], which in turn influences the outcome

of the septic patient [10]. Additionally, persistence of lactate levels above normal is

associated with higher mortality rates in patients with severe sepsis or septic shock

[20,22,23]. Therefore, it is possible that duration of hyperlactataemia outperforms single

lactate measurements in predicting outcome. In chapter 6 the relationship between

hyperlactataemia and organ failure as described by the Sequential Organ Failure

Assessment (SOFA) is described in an ICU population of 2251 patients [24-26], in particular

in relation to final outcome.

Both ScvO2 and lactate are, to a greater or lesser extent, a reflection of a possible

oxygen debt in critically ill patients. Above that, both values have been used in a diagnostic

and therapeutic manner. However, normal values do not guarantee adequate tissue

oxygenation and other circulatory parameters are needed to evaluate either treatment with

catecholamines or resuscitation efforts altogether. One parameter that has been described in

this context is the central venous-to-arterial carbon dioxide difference (pCO2 gap) [27]. The

pCO2 gap reflects adequacy of blood flow [28,29], i.e. cardiac output (CO). CO, combined

with other variables such as vital signs and ScvO2, gives us an idea on cardiac performance

and physiological reserve of the patient. Hence, the pCO2 gap may be of additional value

during resuscitation of critically ill patients. The final chapter of this thesis explores the place

of the pCO2 gap in the resuscitation of patients with severe sepsis or septic shock during the

first 24 hours after ICU admittance.

References

1. Rady MY, Rivers EP, Novak RM: Resuscitation of the critically ill in the ED:

responses of blood pressure, heart rate, shock index, central venous oxygen

saturation, and lactate. Am J Emerg Med 1996, 14:218-225.

2. Wo CC, Shoemaker WC, Appel PL, Bishop MH, Kram HB, Hardin E: Unreliability of

blood pressure and heart rate to evaluate cardiac output in emergency resuscitation

and critical illness. Critical Care Medicine 1993, 21: 218-223.

3. Vincent JL, De Backer D: Oxygen uptake/oxygen supply dependency: fact or fiction?

Acta Anaesthesiol Scand Suppl 1995, 107:229-237.

4. Kandel G, Aberman: A Mixed venous oxygen saturation: its role in the assessment of

the critically ill patient. Arch Int Med 1983, 143: 1400-1402.

5. Connors AF Jr, Speroff T, Dawson NV, Thomas C, Harrell Jr FE, Wagner D, Desbiens N,

Goldman L, Wu AW, Califf RM, Fulkerson Jr WJ, Vidaillet H, Broste S, Bellamy P, Lynn J,

Knaus WA: The effectiveness of right heart catheterization in the initial care of

critically ill patients. SUPPORT investigators. JAMA 1996, 276: 889-897.

6. Sakr Y, Vincent JL, Reinhart K, Payen D, Wiedermann CJ, Zandstra DF, Sprung CL: Use

of the pulmonary catheter is not associated with worse outcome in the ICU. Chest

2005, 128: 2722-2731.

7. Harvey S, Harrison DA, Singer M, Ashcroft J, Jones CM, Elbourne D, Brampton W,

Williams D, Young D, Rowan K: Assessment of the clinical effectiveness of

pulmonary artery catheters in management of patients in intensive care (PAC-Man):

a randomised controlled trial. Lancet 2005, 366: 472-477.

8. Vincent JL: So we use less pulmonary artery catheters – But why? Crit Care Med

2011; 39: 1820-1822.

9. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Tomlanovich M; for the

Early Goal-Directed Therapy Collaborative Group: Early Goal-Directed Therapy in the

treatment of severe sepsis and septic shock. N Engl J Med 2001, 345:1368-1377.

10. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J,

Keh D, marshall J, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM; for

Surviving Sepsis Campaign: Surviving Sepsis Campaign guidelines for management

of severe sepsis and septic shock. Crit Care Med 2004, 32:858-873.

11. Varpula M, Karlsson S, Ruokonen E, Pettilä V: Mixed venous oxygen saturation cannot

be estimated by central venous oxygen saturation in septic shock. Intensive Care

Med 2006, 32:1336-1343.

12. Chawla LS, Zia H, Guttierez G, Katz NM, Seneff MG, Shah M: Lack of equivalence

between central and mixed venous oxygen saturation. Chest 2004, 126:1891-1896.

13. Rivers E: Mixed vs central venous oxygen saturation may be not numerically equal,

but both are still clinically useful. Chest 2006, 129:507-508.

14. Davison DL, Chawla LS, Selassie L, Jones EM, McHone KC, Vota AR, Junker C, Sateri S,

Seneff MG: Femoral-based central venous oxygen saturation is not a reliable

substitute for subclavian/internal jugular-based central venous oxygen saturation in

patients who are critically ill. Chest 2010; 138: 76-83.

15. Levy MM, Macias WL, Vincent JL, Russell JA, Silva E, Trzakoma B, Williams MD: Early

changes in organ function predict eventual survival in severe sepsis. Crit Care Med

2005, 33: 2194-2201.

16. Gutierrez G, Williams JD: The riddle of hyperlactataemia. Crit Care 2009, 13: 176.

17. Bellomo R, Reade MC, Warrilow SJ: The persuit of a high central venous oxygen

saturation in sepsis: growing concerns. Crit Care 2008, 12: 130.

18. Abramson D, Scalea TM, Hitchcock R, Trooskin SZ, Henry Sm, Greenspan J: Lactate

clearance and survival following injury. J Trauma 1993, 35: 584-589.

19. Donati A, Cornacchini O, Loggi S, Caporelli S, Conti G, Falcetta S, Alò F, Pagliariccio G,

Bruni E, Preiser JC, Pelaia P: A comparison among portal lactate, intramucosal

sigmoid pH, and deltaCO2 (PaCO2 – regional Pco2) as indices of complications in

patients undergoing abdominal aortic aneurysm surgery. Anesth Analg 2004, 99:

1024-1031.

20. Callaway DW, Shapiro NI, Donnino MW, Baker C, Rosen CL: Serum lactate and base

deficit as predictors of mortality in normotensive elederly blunt trauma patients. J

Trauma 2009, 66: 1040-1044.

21. Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL: Serial blood lactate levels can

predict the development of multiple organ failure following septic shock. Am J Surg

1996, 171: 221-226.

22. Bakker J, Coffernils M, Leon M, Gris P, Vincent JL: Blood lactate levels are superior to

oxygen-derived variables in predicting outcome in human septic shock. Chest 1991,

99: 956-962.

23. Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, Tomlanovich

MC: Early lactate clearance is associated with improved outcome in severe sepsis

and septic shock. Crit Care Med 2004, 32: 1637-1642.

24. Peres Bota D, Melot C, Lopes Ferreira F, Nguyen Ba V, Vincent JL: The Multiple Organ

Dysfunction Score (MODS) versus the Sequential Organ Failure Assessment

(SOFA) score in outcome prediction. Intensive Care Med 2002, 28: 1619-1624.

25. Cabré L, Mancebo J, Solsona JF, Saura P, Gich I, Blanch L, Carrasco G, Martín, Bioethics

Working Group of the SEMICYUC: Multicenter study of the multiple organ dysfunction

syndrome in intensive care units - the usefulness of the Sequential Organ Failure

Assessment scores in decision making. Intensive Care Med 2005, 31: 927-93.

26. Vincent JL, de Mendonca A, Cantraune F, Moreno R, Takala J, Suter PM, Sprung CL,

Colardyn F, Blecher S: Use of the SOFA score to assess the incidence of organ

system dysfunction/failure in intensive care units: results of a multi-center,

prospective study. Crit Care Med 1998, 26: 1793-1800.

27. Vallée F, Vallet B, Mathe O, Parraguette J, Mari A, Silva S, Samii, Fourcade O, Genestal:

Central venous-to-arterial carbon dioxide difference: an additional target for goal-

directed therapy in septic shock? Intensive Care Med 2008, 34: 2218-2225.

28. Johnson BA, Weil MH: Redefining ischemia due to circulatory failure as dual defects

of oxygen deficits and of carbon dioxide excesses. Crit Care Med 1991, 19: 1432-

1438.

29. Weil MH, Rackow EC, Trevino R, Grundler W, Falk JL, Griffel MI: Difference in acid-

based state between venous and arterial blood during cardiopulmonary

resuscitation. N Engl J Med 1986, 315: 153-156.

Chapter 1

The use of venous oxygen saturations as a goal:

a yet unfinished puzzle

A clinical review

Paul van Beest, Götz Wietasch,

Thomas Scheeren, Peter Spronk, Michaël Kuiper

Abstract


systemic oxygen delivery and oxygen demand. Venous oxygen saturations represent this

relationship between oxygen delivery and oxygen demand and can therefore be used as

additional parameter to detect an impaired cardiorespiratory reserve. However, before

appropriate use of venous oxygen saturations one should be aware of its physiology. This

article describes the physiology of venous oxygen saturations and the use of both mixed

venous oxygen saturation and central venous oxygen saturation in a variety of clinical

settings.

Although venous oxygen saturation has been subject of research for many years,

increasing interest arose especially in the last decade for its use as a therapeutic goal in

critically ill patients and during the perioperative period. Also, there has been debate on

differences between mixed and central venous oxygen saturation and their

interchangeability. Both mixed and central venous oxygen saturation are clinically useful but

both variables should be used with insightful knowledge and caution. In general, low values

warn the clinician about cardiocirculatory or metabolic impairment and should urge for further

diagnostics and appropriate action, whereas normal or high values do not rule out persistent

tissue hypoxia. The use of venous oxygen saturations seems especially useful in the early

phase of disease or injury. Whether venous oxygen saturations should be measured

continuously remains unclear. Especially continuous measurement of central venous oxygen

saturation as part of treatment protocol has shown to be a valuable strategy in the

emergency department and in cardiac surgery. In clinical practice venous oxygen saturations

should always be used in combination with vital signs and other relevant endpoints.

Methods

We performed a search of the PUBMED database from 1980 to 2010 using

combinations of the following terms: [SvO2, ScvO2, venous oxygen saturation, venous

saturation, critically ill, shock, septic shock, high risk surgery, surgery, operation]. The articles

published in English were included when published in a peer-reviewed journal. The clinical

investigations had to concern adults. Additionally, bibliographies of relevant articles were

screened as well.

Physiology

Understanding the physiology of venous saturations is essential for its effective

application in critically ill patients and during the perioperative period.

SvO2 depends on arterial oxygen saturation (SaO2), the balance between oxygen

demand (VO2) and cardiac output (CO), and hemoglobin levels. According to the Fick

principle [8], SvO2 can be described by the following formula:

SvO2 = [SaO2 – VO2 / CO ] [1 / Hb x 1,34]

Increased VO2 will be compensated by increased CO. If this is not adequate, i.e. if O2

demand is not met, elevated oxygen extraction in the peripheral tissues occurs and

consequently SvO2 will drop. Thus, SvO2 reflects the balance between oxygen delivery and

oxygen demand [9]. The normal range for SvO2 is 65 to 75% [4,10]. Low SvO2 is predictive of

bad outcome [4,11], whereas normal or supra normal SvO2 (or ScvO2) values do not

guarantee adequate tissue oxygenation [12,13]. If tissue is not capable of extracting oxygen,

e.g. in case of shunting and cell death, venous return may have high oxygen content despite

persistent cellular hypoxia.

A variety of physiological and pathological changes may influence venous saturation

(figure 1) and thus require different therapeutic interventions. Recognition of the aetiology of

any derangement is obligatory for the safe use of venous saturation as therapeutic goal.

Figure 1. Multiple physiologic, pathologic and therapeutic factors may influence the value

of central venous oxygen saturation.

Central versus mixed venous oxygen saturation (table 1)

In general there has been considerable debate on equality or interchangeability of

ScvO2 and SvO2 [14-16]. In critically ill patients substituting SvO2 by ScvO2 results in large

variability [16-21]. This could in part be explained by modifications of blood flow distribution

criticall illness

injury

perioperative period

↓ venous oxygen saturations

↓ O2 delivery

anemia

hemorrhage

hypoxia

hypovolemia

heart failure

↑ O2 consumption

agitation

pain

fever

shivering

respiratory failure

↑ metabolic demand

↑ venous oxygen saturations

↑ O2 delivery

oxygen therapy

blood transfusion

intravenous fluid

inotropics

↑ cardiac output

↓ O2 consumption

sedation

analgesia

hypothermia

mechanical ventilation

↓ O2 extraction

shunting (sepsis)

cell death

and oxygen extraction by brain and splanchnic tissue. In this situation, ScvO2 may provide

the false impression of adequate body perfusion. Also, whether a positive ScvO2 – SvO2

gradient can be used as a marker of greater O2 utilization and predictor of survival remains

subject of debate [20,22,23].

In contrast, others have stated that ScvO2 could indeed be used as a substitute for

SvO2 [24-26]. For example, Reinhart et al. [24] performed continuous measurements of

venous oxygen saturations in anesthetized dogs over a wide range of hemodynamic

conditions, including hypoxia, haemorrhage and resuscitation, and described close tracking

between ScvO2 and SvO2 [24]. However, correlation was lowest during hypoxia, one of the

areas of greatest clinical interest. Nevertheless, precise determination of absolute values for

SvO2 from ScvO2 was not possible, as was seen before [21,27-29].

Additionally, the relationship between cardiac output (CO) or cardiac index (CI) and

venous saturations has been evaluated in critically ill patients. So far, for both SvO2 and

ScvO2 the results were inconclusive. Larger trials are needed before clinical

recommendations can be made regarding their clinical use [19,30-33].

Table 1. Studies comparing mixed venous oxygen saturation and central venous oxygen saturation

study design and subjects results conclusions

Varpula et al [14] n=16; septic shock; ICU

72 paired samples

mean SvO2 below mean ScvO2 at all time points;

bias of difference 4.2%;

95% limits of agreement -8.1 to 16.5%;

difference correlated with CI and DO2

difference between ScvO2 and SvO2 varied highly;

SvO2 cannot be estimated on basis of ScvO2

Martin et al [16] n=7; 580 comparative measurements;

critically ill patients; ICU

with and without interventions

difference were equal or greater than 5%

in 49% during periods of stability and

in 50% during periods with interventions

ScvO2 monitoring not reliable

Chawla et al [17] n=32 postsurgical, n=21 medical;

ICU

SvO2 consistently lower than ScvO2;

mean (±SD) bias -5.2 ± 5.1%

SvO2 and ScvO2 not equivalent; substitution of ScvO2

for SvO2 in calculation of VO2 resulted in

unacceptably large errors

Kopterides et al [18] n=37; septic shock mean SvO2 below mean ScvO2;

mean bias -8.5%;

95% limits of agreement -20.2 to 3.3%

ScvO2 and SvO2 not equivalent in septic shock;

calculation of VO2 resulted in unacceptably

large errors

Ho et al [19] n=20; cardiogenic or septic shock ScvO2 overestimated SvO2 with mean bias 6.9%;


changes did not follow the line of perfect agreement

ScvO2 and SvO2 are not interchangeable numerically

van Beest et al [20] n=53; 265 paired samples;

sepsis; ICU

multi centre

mean SvO2 below mean ScvO2 at all time points;

bias of difference 1.7%


identical results for change in ScvO2 and SvO2

ScvO2 does not reliably predict SvO2 in sepsis

trend of ScvO2 not superior in this context

Scheinmann et al [21] n=24; critically ill cardiac patients;

CCU

ScvO2 > SvO2 in shock

changes in ScvO2 reflect changes in SvO2 (r=0.90);

ScvO2 from right atrium is similar to SvO2 (r=0.96)

SvO2 consistently lower than ScvO2

poor correlation in heart failure or shock

changes in ScvO2 reflect changers in SvO2

Dueck et al [25] n=70; 502 comparative sets;

neurosurgery

95% limits of agreement 6.8% to 9.3% for single values

correlations between changes of SvO2 and ScvO2:

r=0.755, p < 0.001

numerical ScvO2 values not equivalent to SvO2 in

varying hemodynamic conditions; trend of ScvO2

may be substituted for the trend of SvO2

Reinhart et al [26] n=32; critically ill patients; ICU

continuous parallel measurements

ScvO2 closely paralleled SvO2;

ScvO2 averaged (±SD) 7±4% higher than SvO2

ScvO2 changed in parallel in 90% when SvO2 changed > 5%

continuous fiberoptic measurement of ScvO2

potentially reliable tool to rapidly warn of acute

change in the oxygen supply / demand ratio

Ladakis et al [28] n=31 surgical and n=30 medical;

critically ill patients; ICU

significant difference between mean ScvO2 and SvO2

r=0.945 for total population

ScvO2 and SvO2 are closely related and

interchangeable for initial evaluation

Tahvanainen et al [29] n=42; critically ill patients; ICU

ScvO2 as representative of real

changes in pulmonary shunt

correlation between PA blood samples and both

superior vena cava and right atrial blood samples

ScvO2 can replace SvO2;

exact SvO2 value can only be measured from PA

CCU, cardiac care unit; ScvO2, central venous oxygen saturation; SvO2, mixed venous oxygen saturation; ICU, intensive care unit; VO2, oxygen consumption; CI,

cardiac index; DO2, oxygen delivery; PA, pulmonary artery.

Clinical use of venous oxygen saturations (table 2)

Cardiac failure

Venous oxygen saturations have been shown to have diagnostic, prognostic, and

therapeutic qualities in critically ill patients having an acute myocardial infarction. Mixed

venous oxygen saturation was particularly reduced in patients with cardiogenic shock or left

ventricular failure. Patients with cardiac failure are unable to increase cardiac output during

periods of increased oxygen need. Changes in oxygen demand will therefore only be

compensated by changes in oxygen extraction in the same direction and indicated by inverse

changes in venous oxygen saturations. Consequently, a drop in venous oxygen saturations

will be a marker of cardiac deterioration. Patients with low venous oxygen saturations in early

disease stage may considered to be in shock [34,35]. Also, patients with sepsis and known

decreased left ventricular function seem to benefit from early goal-directed therapy (EGDT)

when treated for sepsis [36] according to the Surviving Sepsis Campaign guidelines [37].

Finally, in the setting of cardio pulmonary resuscitation (CPR) a ScvO2 of 72% is highly

predictive of return of spontaneous circulation [38].

Trauma

In the initial assessment of trauma patients an adequate judgement of possible blood

loss is essential. Compared to conventional parameters venous oxygen saturations are

superior in predicting blood loss [39,40]. Moreover, after major trauma with brain injury ScvO2

values below 65% in the first 24 hours are associated with higher mortality (28-days

mortality; 31.3% vs. 13.5%) and prolonged hospitalization (45 vs. 33 days) [41].

Table 2. Studies describing central venous oxygen saturation in clinical settings

study design and subjects results conclusions

Rady et al [1] n=36; critically ill patients; ED additional therapy is needed after hemodynamic

stabilization to normal blood pressure and heart rate

ScvO2 and can be utilized to guide

thearpy

Pope et al [13] n=619 registries treated with EGDT

observational study

groups: ScvO2 < 70%, ScvO2 71-89%, ScvO2 > 90%

multivariate analysis: initial high ScvO2 higher mortality

also high ScvO2 values predictive for

mortality

Ander et al [35] controls n=17, high-lactate group

n=22, low lactate group n=5;

chronic congestive heart failure;

ED

ScvO2 lower in high lactate group than in low lactate group

(32±12% vs. 51±13%) and control (60±6%); after treatment

significant decrease of lactate and increase in ScvO2

in the high lactate group compared to low lactate group

once patients with decompensated

end-stage congestive heart failure

are identified, aggressive alternative

management is needed

Scalea et al [40] n=26, trauma patients with

suggested blood loss

despite stable vital signs 39% of the patients had ScvO2 <65%;

these patients required more transfusions;

superiority ScvO2 to predict blood loss

ScvO2 reliable and sensitive method for

detecting blood loss;

it is a useful tool in the evaluation

Di Filippo et al [41] n=121 brain injury after trauma;

non-controlled study

nonsurvivors showed higher lactate, lower ScvO2 values;

patients with ScvO2 ≤65% showed higher 28-day mortality,

ICU LOS and hospital LOS than patients with ScvO2 >65%

ScvO2 <65% in first 24 hours in patients

with major trauma is associated with

prolonged LOS and higher mortality

Pearse et al [65] n=118, major surgery after multivariate analysis lowest CI and lowest ScvO2 were

associated with post-operative complications;

optimal ScvO2 cut-off for morbidity prediction:64.4%

oxygen consumption is also an important

determinant of ScvO2; reductions in

ScvO2 independently associated with

post-operative complications

Rivers et al [73] n=263; RCT; EGDT vs. controls

severe sepsis, septic shock; ED

EGDT (goal: ScvO2 ≥ 70%) showed better survival

(absolute 16%), lower lactate; more fluids,

red cell transfusion and inotropics

EGDT provides benefits to outcome

Trzeciak [74] n=16 pre-EGDT

n=22 EGDT

less PAC utilization; more fluids and dobutamine used;

similar costs

EGDT endpoint can reliably be achieved

Kortgen [75] n=30 controls; n=30 septic shock

implementation procedure

septic shock

use of dobutamine, insulin, hydrocortisone and aPC

increased; amount of fluids and packed bloods cells

unaffected; mortality in lower after implementation

implementation of sepsis bundle feasible

survival benefit

Jones [76] n=79 pre-intervention

n=77 post-intervention

ED

controls: more renal failure at baseline

greater crystalloid volume and vasopressor infusion

mortality 18 vs. 27%

mortality reduction

Micek [78] n=60 before implementation

n=60 after implementation

ED

more appropriate antimicrobial regimen

more fluids, more vasopressors

less vasopressor by time of transfer to ICU

shorter hospital LOS

lower 28-day mortality

Shapiro [80] n=51 historical controls

n=79 septic shock

patients received more fluids, earlier antibiotics,

more vasopressors, tighter glucose control;

not more packed blood cells

implementation sepsis protocol feasible

no survival benefit

Jones et al [94] multicentre, randomized; n=300

severe sepsis, septic shock

goals: lactate clearance vs. ScvO2

higher in hospital mortality ScvO2;

no significant difference (predefined -10% threshold)

no significant different mortality

between normalization of lactate

clearance compared to normalization

ScvO2

ED, emergency department; ScvO2, central venous oxygen saturation; EDGT, early goal-directed therapy; RCT, randomized controlled trial; ICU LOS, length of stay in

intensive care unit; hospital LOS, length of stay in hospital; CI, cardiac index; SAPS II, simplified acute physiology score; ICU, intensive care unit.

High-risk surgery

In cardiac surgery patients, SvO2 has been shown to be superior to mean arterial

pressure (MAP) and heart rate as qualitative warning sign of substantial hemodynamic

deterioration. However, results on predictive value of SvO2 for CO in clinical settings are

inconsistent [42-44]. Nevertheless, continuous SvO2 monitoring enables the early diagnosis

of occult bleeding or could show poor tolerance of a moderate anaemia due to the inability of

the patient with chronic heart dysfunction or preoperative negative inotropic treatment (e.g.

beta-blockers) to increase CO in the face of anaemia. Furthermore, temporary decreases of

SvO2 values after cardiac surgery are of prognostic value and may predict the development

of arrhythmias [45-47]. Also, probably due to increased oxygen extraction ratio (O2ER)

decreased SvO2 values during weaning from mechanical ventilation are predictive for

extubation failure [48-50]. Finally, good predictive values of SvO2 for mortality have been

described [51,52]. This suggests beneficial effects of SvO2 monitoring, at least during and

after cardiac surgery.

Goal Directed Therapy (GDT) has been shown to improve outcome after major

general surgery [53] Originally, the goals in the protocol group were supra-normal

hemodynamic and oxygen transport values (CI > 4.5 L/min/m2, DO2 > 600 ml/min/m2, VO2 >

170 ml/min/m2). In this group a significant reduction of complications, hospital stay, duration

of mechanical ventilation and mortality was achieved when the PAC was placed

preoperatively [54]. However, such strict predefined concept holds certain risks and should

not be translated to all patients [55-57]. Meta-analyses of hemodynamic optimization in high

risk patients revealed hemodynamic optimization to be beneficial only when interventions

were commenced before development of organ failure [58,59]. Several of the studies

described showed improved outcome, possibly including long-term survival, when GDT was

commenced before surgery [54,60-62]. Maybe due to methodological shortcomings, a multi-

centre trial that randomised surgical patients to PAC guided or conventional management

failed to show a difference in outcome [63,64]. More recently a reduction in post-operative

complications and duration of hospital stay was described when GDT was used post-

operatively [65-67]. However, the abovementioned findings do not provide definite answers

on how to use venous saturations as a therapeutic goal. Only one interventional trial used

ScvO2 as a therapeutic goal in perioperative care [68]. After achieving predefined goals for

arterial pressure, urine output, and central venous pressure, the intervention group received

therapy to achieve the additional goal of an estimated oxygen extraction ratio < 27%. Fewer

patients developed organ failure in the ScvO2 group [68].

.

Sepsis and septic shock

In a large multi-centre study 3 different cohorts of a very heterogeneous population of

critically ill patients were compared for survival after different strategies for hemodynamic

therapy had been applied: control vs. supra-normal values for the cardiac index (>

4.5L/min/m2) or normal values for mixed venous saturation. In total, the anticipated goal was

only achieved in one third of the patients. There was no significant reduction in morbidity or

mortality in any group [69]. An important reason for this may be the late timing of the

intervention, i.e. after occurrence of organ failure, implying that all patients suffered severe

damage and received significant treatment before inclusion.

Global tissue hypoxia as a result from systemic inflammatory response or circulatory

failure is an important indicator of shock preceding multiple organ dysfunction syndrome

(MODS). The development of MODS predicts outcome of the septic patient [37]. Treatment

strategies aimed at restoring the balance between DO2 and VO2 by maximizing DO2 have not

been successful [57,69,70].

In line with studies over several decades [1,21,27,35,40,71] and based on

recommendations [72] Rivers et al. randomized 263 patients with severe sepsis or septic

shock to standard therapy or EGDT. Compared with the conventionally treated group, the

ScvO2 guided group received more fluids, more frequently dobutamine, and more blood

transfusion during the first 6 hours. This resulted in an absolute reduction in 28-day mortality

of 16% [73].

A large amount of studies that implemented certain treatment protocols at the

emergency department, including antibiotic therapy and tight glucose control for example,

[74-79] showed significant decrease in mortality. EGDT endpoints (CVP 8-12 mmHg, MAP ≥

65 mmHg, and ScvO2 ≥ 70%) can well be achieved in an ED setting suggesting that a

multifactor approach is a useful strategy in the treatment of sepsis [74-80]. Of note, three of

these studies described similar populations with high percentage end-stage renal disease in

the control group being prone for higher mortality [76,77,79,81]. Although attainment of an

ScvO2 >70% has been reported as prominent factor for survival [82] several studies in which

EGDT without that specific target was used were able to achieve a survival benefit as well

[83-85]. In summary, as shown by Nguyen et al [86], the use of (modified) EGDT implies

early recognition of the critically ill patient and enforces continuous reassessment of

treatment. This seems to be the greatest gain in the treatment of patients with severe sepsis

or septic shock over the last decade.

Earlier studies that enrolled patients admitted at the intensive care unit (ICU) were

unable to show a decrease in mortality after aggressive hemodynamic optimization [57,69].

In contrast, more recent studies that used modified EGDT protocols were able to show an

significant decrease in mortality [85,87,88], suggesting that compliance to dedicated sepsis

bundles after the ED stage can still be useful.

However, low incidences of low ScvO2 values at ICU admission [89] or emergency

department (ED) presentation [90] do occur together with baseline mortality compared to the

original EGDT study [73,89,90]. For clinical appreciation of the abovementioned results a

thorough look into the data is needed. Interestingly, in the EGDT study [73] less patients

were intubated before first ScvO2 sampling and this could partially explain the difference of

initial ScvO2 values between both studies [73,89]: due to higher DO2 (pre-oxygenation) and

lower VO2 (sedation, paralysis; lower work of breathing) ScvO2 may very well improve in

response to emergency intubation in the majority of patients [91]. This partially explaines the

differences between populations [73,89,90] and provides another piece in the puzzle on the

value of ScvO2 [93]. Nevertheless, applicability of the results of the EGDT trial may be

dependent on geographical setting and underlying health care system [92,93].

Additionally, no difference in outcome was found between a resuscitation protocol

based on lactate clearance and a ScvO2 based protocol [94] and ScvO2 optimization does

not always exclude a decrease in lactate levels [95]. Also, the pursuit of ScvO2 values >70%

does not always seem to be the optimal solution. Recent data suggest that also patients with

initially high ScvO2 values may have adverse outcomes [12,13], probably due to impaired

oxygen utilization. High ScvO2 values may thus represent an inability of the cells to extract

oxygen or microcirculatory shunting in sepsis [96].

Finally, as a reflection of increased respiratory muscles O2ER a reduced ScvO2 or

SvO2 predicts extubation failure in difficult-to-wean patients [48,97]. However, a successful

intervention to increase ScvO2 in this context is not known yet. Nevertheless, it is

conceivable that in the future ScvO2 will be used as a parameter in weaning protocols for a

subset of patients [97,98].

Continuous measurement

Should continuous measurement be considered when venous saturations are used

as a therapeutic goal? It may be argued that changes in venous saturations may occur

rapidly, particularly in hemodynamically instable patients, and that discontinuous spot

measurements by drawing intermittent blood samples may miss these changes. Accordingly,

continuous measurement of SvO2 in septic shock patients revealed a higher frequency of

short-term changes in SvO2 in nonsurvivors. Thus, variations in SvO2 could be of prognostic

importance [99]. However, lack of therapeutic guidelines and cost effectiveness issues

[5,7,58] question the clinical use of continuous measurement of SvO2 in critically ill.

Continuous measurement in perioperative care allows detection of fluctuations. Low SvO2

values have been associated with increased complications and morbidity, especially in

cardiac surgery [100] and myocardial infarction and use of a SvO2>70% as a target seemed

promising [38,43].

There are currently two commercially available devices to measure ScvO2

continuously. Continuous ScvO2 measurement as part of treatment protocol has shown to be

a valuable strategy in the ED [71,73] and in cardiac surgery [101]. Additionally, Reinhart et al.

concluded that continuous ScvO2 measurement in the ICU setting is potentially reliable [26].

However, continuous and intermittent measurements of SvO2 or ScvO2 have never been

compared systematically.

Conclusions

The on-going debate on differences between SvO2 and ScvO2 and their

interchangeability should focus on well defined populations. Both SvO2 and ScvO2 are

clinically useful but both variables should be used with knowledge and caution. Evaluating

the available evidence in a clinical setting, we conclude that low venous oxygen saturations

are an important warning sign of the inadequacy of systemic oxygen delivery to meet oxygen

demands. Low values may warn the clinician about cardiocirculatory or metabolic impairment

and should urge for further diagnostics and appropriate action, whereas normal or high

values do not rule out persistent tissue hypoxia. Based on the numerous clues for its

usefulness referred in this article the use of venous oxygen saturations seems especially

useful in the early phase of disease or injury. In clinical practice venous oxygen saturations

should always be used in combination with vital signs and other relevant endpoints.

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Chapter 2

The incidence of low venous oxygen saturation

on admission in the ICU: a multicenter

observational study in the Netherlands

Paul van Beest, Jorrit Jan Hofstra, Marcus Schultz,

Christiaan Boerma, Peter Spronk, Michaël Kuiper

Abstract

Introduction Low mixed or central venous saturation (S(c)vO2) can reveal global tissue

hypoxia and therefore can predict poor prognosis in critically ill patients. Early goal directed

therapy (EGDT), aiming at a ScvO2 ≥ 70%, has been shown to be a valuable strategy in

patients with sepsis or septic shock and is incorporated in the Surviving Sepsis Campaign

guidelines.

Methods We determined central venous pressure (CVP), hematocrit, pH, lactate and ScvO2

or SvO2 in a heterogeneous group of critically ill patients early after admission to the

intensive care units (ICUs) in 3 Dutch hospitals.

Study design Prospective observational multicenter study.

Results Data of 340 acutely admitted critically ill patients were collected. The mean SvO2-

value was > 65% and the mean ScvO2 was >70%. With mean CVP of 10.3 ± 5.5 mmHg,

lactate plasma levels of 3.6 ± 3.6 and APACHE II-scores of 21.5 ± 8.3, the in-hospital

mortality of the total heterogeneous population was 32.0%. A subgroup of septic patients (n =

125) showed a CVP of 9.8 ± 5.4 mmHg, mean ScvO2 values of 74.0 ± 10.2% - where only

1% in this subgroup revealed a ScvO2-value < 50% - and lactate plasma levels of 2.7 ± 2.2

mmol/L with APACHE II-scores 20.9 ± 7.3. Hospital mortality of this subgroup was 26%.

Conclusion The incidence of low ScvO2 values on acutely admitted critically ill patients is

low in Dutch ICUs. This is especially true for patients with sepsis / septic shock.

Introduction

Global tissue hypoxia as a result from systemic inflammatory response or circulatory

failure is an important indicator of shock preceding multiple organ dysfunction syndrome

(MODS). The development of MODS predicts outcome of the septic patient [1].

Unrecognized and untreated global tissue hypoxia increases morbidity and mortality.

Accurate detection of global tissue hypoxia is therefore of vital importance. Physical findings,

vital signs, measuring central venous pressure (CVP) and urinary output are of the utmost

importance, but not always sufficient for accurate detection of global tissue hypoxia [2,3].

It is now generally accepted that a decreased central venous saturation (ScvO2)

obtained from a central venous catheter, can reveal a mismatch between oxygen supply and

oxygen demand, hence global tissue hypoxia [1]. Decreased values predict poor prognosis

after cardiovascular surgery [4], in severe cardiopulmonary disease [5], and in septic or

cardiogenic shock [6,7]. ScvO2 and SvO2 (mixed venous oxygen saturation) therefore can be

used as hemodynamic goals during resuscitation. According to Rivers et al. [8] hemodynamic

optimization demands ‘early goal-directed therapy’ (EGDT), including ScvO2-guided

treatment. It was concluded that goal-oriented manipulation of cardiac preload, afterload and

contractility, to achieve a balance between systemic oxygen delivery and oxygen demand is

a valuable strategy in patients with sepsis or septic shock during the resuscitation period in

the emergency department (ED) [8]. More recently, as a result of this study, an EGDT

treatment protocol was included in the ‘Surviving Sepsis Campaign’ guidelines [1]. Also,

several studies on implementation of such a protocol, partially in combination with other

recommendations, have been published over the last years [9-11].

Based on clinical experience it seemed that the syndrome targeted in the EGDT study

[8], was not very common in our ICUs and thus EGDT not being commonly indicated. Main

purpose of this study was to determine the incidence of low ScvO2 values in our geographical

setting. We monitored a heterogeneous group of critically ill patients during unplanned

admission in 3 Dutch multidisciplinary ICUs. Also, illustratively, we compared the subgroup of

septic patients with the population of septic patients as described by Rivers et al [8], with

respect to ScvO2 and other base-line characteristics.

Methods

Study centers

We studied ICU populations in one academic ICU [Academic Medical Center (AMC)

in Amsterdam, The Netherlands] and two nonacademic ICUs [Gelre Hospital (GH) location

Lukas in Apeldoorn, The Netherlands; Medical Center Leeuwarden (MCL) in Leeuwarden,

The Netherlands]. The AMC is a large teaching hospital where the ICU is a 28-bed “closed

format” department in which medical/surgical patients, including cardiothoracic and

neurosurgical patients, are being treated. The GH is an affiliated teaching hospital where the

ICU is a 10-bed “closed format” department. The MCL is a large general teaching hospital in

the north of The Netherlands, with a 14-bed “closed format” mixed medical / surgical ICU,

including cardiothoracic patients.

Patients and data collection

Between January 2006 and March 2007 a total of 340 patients, all 18 years or older,

with a clinical indication for a central venous catheter (CVC) [BD Medical Systems,

Singapore], pulmonary artery catheter (PAC) [Edwards Lifesciences LLC, Irvine, CA, USA] or

Continuous Cardiac Output (CCO) catheter [Arrow Deutschland GmbH, Erding, Germany]

(which measures SvO2 continuously) were recruited. Indication for a central venous, PAC or

CCO catheter was left to the discretion of the attending physician. The patients arrived at the

ICU either directly from the ED, from the general ward, or after acute surgery with severe

sepsis, septic shock or cardiogenic shock, respiratory failure, central nervous problems, and

other acute conditions. In the EDs there was no standardized protocol for hemodynamic

treatment of septic patients. Fluid resuscitation was mostly guided by blood pressure

monitoring. Inotropes were given scarcely at our EDs. Intubation on the ED was also

uncommon. In the operating theatres no ScvO2 / SvO2 measurements took place, nor any

kind of goal directed therapy was implemented. All patients were treated according to

standard practice for the ICU. Exclusion criteria were elective surgery and age < 18 years.

Collecting data for observational study without informed consent was approved by the

Medical Ethics Committees of all 3 hospitals.

Measurements of systolic arterial pressure (SAP), mean arterial pressure (MAP) and

central venous pressure (CVP) were recorded immediately after arrival at the ICU.

Hematocrit (Hct), lactate plasma levels and pH were determined from the first obtained

arterial blood sample at the ICU.

APACHE II-score [12] and SOFA-score [13] at the time of admission at the ICU were

collected.

Statistical analysis

The statistical package for the social sciences (SPSS 15.0.1 for Windows) was used

for statistical analysis. All data were tested for normal distribution with the Kolmogorov-

Smirnov test before further statistical analysis. Differences between both populations were

assessed using Student’s paired t-test (normally distributed data). Data were displayed as

mean ± SD. Statistical significance was assumed at p < 0.05.

Results

Patients

A heterogeneous population with a total of 340 critically ill patients was evaluated in

the three participating ICUs (table 1). The patients arrived at the ICU either directly from the

ED (n=135; 40%), from the general ward (n=126; 37%) or after acute surgery (n=79; 23%).

To determine ScvO2 or SvO2, central venous or mixed venous oxygen saturation was

measured as early as possible after insertion of a central venous catheter (n=263) or

pulmonary artery / CCO catheter (n=77). The vast majority (93%) of the patients were

enrolled within 6 hours after presentation in the ER. More than 99% of all the data was

obtained within 2 hours after ICU admission. The numbers of measurements of central or

mixed oxygen venous saturation were not normally distributed between the three ICUs. In all

three hospitals the mean SvO2 was higher than 65% and mean ScvO2 was higher than 70%.

Overall in-hospital mortality of our population was 32.0%.

In 263 patients venous oxygen saturation was measured centrally (table 2). Mean

ScvO2 was 72.0 ± 12.3%. Thirty-eight patients (14%) had a ScvO2 < 60%, and only 14 (5%)

patients had a ScvO2 < 50%. While only 1 patient of the latter was in septic shock, in-hospital

mortality of these 14 patients was 57% (8/14).

Septic patients

In patients with sepsis or septic shock (n = 150) central venous oxygen was

measured in 125 patients and mixed venous oxygen saturation was measured in 25 patients.

The in-hospital mortality of our septic patients was 27%. Seventy-three patients arrived at the

ICU from the general ward (n=73; 49%). The mean ScvO2 value was normal: 74.0 ± 10.2%.

Only eight (6%) patients had a ScvO2 < 60%, and 1 (1%) < 50% (table 2).

Table 1. Distribution of clinical problems in the three ICUs

admission diagnosis MCL

(n=93)

GH

(n=138)

AMC

(n=109)

total

(n=340)

Sepsis/septic shock 47 (51) 64 (46) 39 (36) 150 (44)

Cardiac failure,

cardiac arrest

28 (30)

10

36 (26)

10

31 (28)

17

95 (28)

Respiratory failure 7 (8) 13 (10) 12 (11) 32 (9)

CNS 5 (5) 7 (5) 10 (9) 22 (7)

Other 6 (6) 18 (13) 17 (12) 41 (12)

Data are presented as numbers (percentage); CNS, central nervous system; MCL, Medical Center

Leeuwarden; GH,Gelre Hospital; AMC, Amsterdam Medical Center.

Comparison with the EGDT population [8]

Compared to the Rivers study group our septic patients revealed a significantly higher

ScvO2 (74.0 ± 10.2 vs 48.9 ± 12.3%; p < 0.01), lower lactate plasma levels (2.7 ± 2.2 vs. 7.3

± 4.6 mmol/L; p < 0.01), and lower hematocrit (30.3 ± 6.9 vs. 34.7 ± 8.5%; p < 0.01). Eighty-

three percent (83%) needed endotracheal intubation versus 55% in the EGDT study.

APACHE II-scores were equal (20.9 ± 7.0 vs. 20.9 ± 7.2; p = 1.0). The in-hospital mortality of

this subgroup was 26% (table 2).

Mixed venous oxygen saturation

Measurement of mixed venous oxygen saturation took place in 77 patients. Mean

SvO2 was 68.2 ± 11.8%. Mean lactate was 4.3 ± 4.2 mmol/l; arterial pH was 7.30 ± 0.11.

With mean APACHE II scores of 21.8 ± 7.3 and mean SOFA scores of 9.3 ± 3.6, the in-

hospital mortality was 37% (table 3).

Table 2. Demographic data, variables and outcome data. Comparisons of sepsis patients with

EGDT-study [8] data

variable present cohort

(n=263)

sepsis

(n=125)

EGDT-study

(n=263)

P valuea,b

age (yr) 67.3 ± 14.2 68.9 ± 13.5 65.7±17.2 0.01*

sex (%)

female

male

41

59

38

62

49.4

50.6

heart rate (beats/min) 107 ± 27 115 ± 26 115 ± 29 1.0

CVP (mmHg) 9.8 ± 5.4 10.8 ± 4.9 5.7 ± 8.5 <0.01*

MAP (mmHg) 58 ± 16 60 ± 13 75 ± 25 <0.01*

ScvO2 (%) 72.0 ± 12.3 74.0 ± 10.2 48.9 ± 12.3 <0.01*

lactate (mmol/l) 3.3 ± 3.3 2.7 ± 2.2 7.3 ± 4.6 <0.01*

arterial pH 7.33 ± 0.12 7.35 ± 0.10 7.32 ± 0.18 0.42

hematocrit (%) 31.0 ± 7.0 30.3 ± 6.9 34.7 ± 8.5 <0.01*

APACHE II score 21.5 ± 8.5 20.9 ± 7.3 20.9 ± 7.2 1.0

SOFA score 9.5 ± 3.6 9.6 ± 3.0

in-hospital mortality (%)

standard therapy

EGD therapy

31.0

26.0

46.5

30.5

Data are presented as means ± SD. a

Unpaired T-test, b sepsis subgroup vs. EGDT study.

* Statistically

significant difference. CVP, central venous pressure; MAP, mean arterial pressure; ScvO2, central

venous oxygen saturation.

Of the 25 patients in whom mixed venous oxygen saturation was measured in the

subgroup of septic patients, four (16%) patients showed a SvO2 value <60% on admission.

One patient (4%) had a SvO2 <50%. In this relatively small subgroup mean Hct was 28.2 ±

5.4%, mean MAP 61.0 ± 13.4 mmHg and mean CVP 13.7 ± 4.6 mmHg, while 80% (20/25

patients) needed mechanical ventilation. Mean APACHE II score was 22.2 ± 5.4 and mean

SOFA score10.3 ± 3.7. The in-hospital mortality of this subgroup was 28% (table 3).

Table 3. Demographic data, variables and outcome data; mixed venous

saturations

Variable present cohort

(n=77)

sepsis

(n=25)

age (yr) 61.7 ± 14.0 65.4 ± 10.4

sex (%)

female

male

39

61

52

48

heart rate (beats/min) 102 ± 21 102 ± 21

CVP (mmHg) 13.0 ± 4.9 13.7 ± 4.6

MAP (mmHg) 61 ± 15 61 ± 13

SvO2 (%) 68.2 ± 11.8 72.1 ± 10.8

lactate (mmol/l) 4.3 ± 4.2 3.3 ± 2.3

arterial pH 7.30 ± 0.11 7.32 ± 0.08

hematocrit (%) 29.9 ± 7.1 28.2 ± 5.4

APACHE II score 21.7 ± 7.3 22.2 ± 5.4

SOFA score 9.3 ± 3.6 10.3 ± 3.7

in-hospital mortality (%) 37.0 28.0

Data are presented as means ± SD. CVP, central venous pressure; MAP, mean

arterial pressure; SvO2, mixed venous oxygen saturation.

Discussion

The main result of this present multicenter observational study is the low incidence of

low ScvO2-values (<50%) in septic patients being only 1%. Secondary findings are the

normal mean ScvO2 values and normal mean SvO2 values in critically ill patients, including

patients with severe sepsis or septic shock, on admission in the three ICUs.

Development to severe sepsis and septic shock involves several pathogenic

changes, including global tissue hypoxia as a result of circulatory abnormalities [14].

Especially hemodynamic optimization as a therapeutic target has been studied over the last

decade [2,8,9,15,16]. Based on promising results of earlier studies [2], Rivers et al.

randomized patients with severe sepsis or septic shock to standard therapy or EGDT. The

latter resulted in an absolute reduction in 28-day mortality of 16% [8]. Improvement of the

balance between oxygen delivery (DO2) and oxygen demand (VO2) played an important role.

Other studies however found no reduction of morbidity or mortality as a result of aggressive

hemodynamic optimization, despite higher central venous oxygenation or lower lactate

concentrations [15,16]. Studies that enrolled patients admitted at the ICU were unable to

show decrease in mortality after aggressive hemodynamic optimization [16,17], in contrast to

studies that implemented certain treatment protocols, including antibiotic therapy, at the

emergency department [8,9,11]. In this ICU study we found mean ScvO2 and SvO2 values in

the normal range. Similar figures are described previously in the later stage of sepsis and in

ICU patients [18,19]. This is in concordance with the findings by Gattinoni et al.(67,3-69,7%)

[15] and Bracht et al. (70%) [20].

ScvO2 is a surrogate for SvO2: a significant correlation between the two has been

described21. Although it might still be debatable whether central venous and mixed venous

oxygen saturation are equivalent or not [18,19,21], the clinical importance of both

measurements seems not to be an issue. The Surviving Sepsis Campaign recognizes such

in the resuscitation portion of its severe sepsis and septic shock bundle [1]. Our study design

does not allow any statistical evaluation of ScvO2 compared to SvO2.

APACHE II-scores were similar in comparison to the population described in the

EGDT study [8]. This suggests equal mortality rate predictions. However, physiologic scores

such as APACHE II are dependent on variables that reflect the progression or reversal of

organ dysfunction. Treatment in the ED or operating theatre prior to ICU admission

influences calculation of the physiologic scores. Consequently, the physiologic scores at our

ICUs could partially be underestimated. The significantly higher lactate plasma levels in the

EGDT study suggests a more severe tissue hypoperfusion in that group. However, it is the

clearance rate that is associated with less organ failure and improved survival [22].

Unlike significantly lower mean arterial pressures, the higher CVP and the lower

hematocrit suggest that the septic patients were less hypovolemic compared to the EGDT

population. Relatively high mean blood pressure in the EGDT population suggests an earlier

stage of sepsis with predominating vasoconstriction, or pre-existing hypertension. The higher

CVP in the subgroup with septic patients (n = 125) is partially the result of high percentage of

endotracheal intubation and thus increased intrathoracic pressure before measurement

(83%). In the EGDT study less than 55% needed intubation at admission.

As mentioned earlier, in the present study the patients were treated in the ED, or

elsewhere, before admission at the ICU. This treatment was different from the treatment

given in the EGDT study. Nevertheless, our patients received some fluid therapy.

Transfusion of red blood cells in our EDs was based on clinical suspicion or evidence of

severe blood loss and not on low hematocrit only. Also, a main principle of treatment is to

improve oxygen delivery and this could contribute to higher ScvO2 values in the ICU

population compared to the patients described in the EGDT study and other ED studies.

Other interventions such as sedation and analgesia, most often to facilitate endotracheal

intubation and ventilation might have been beneficial for the balance between oxygen

delivery and oxygen demand. Also the trend of changing ScvO2- and other physiological

values, influencing outcome [23,24], is not taken into account in our study. Of course, all

these factors are important differences between ER populations and ICU populations, but are

not predominating. We are aware that comparison between those populations is limited by

the abovementioned differences.

As a result from the study design, statements about cut-off S(c)vO2 values for

outcome prediction [20,24] or impact on therapeutic intervention, are not possible. Also, we

did not look at the use of vital signs as indicator of tissue oxygenation in comparison to mixed

or central venous saturation. Lack of clear insight of treatment and time spent at the different

EDs, operating theatres or wards is a limitation of our study as well. Nevertheless, since we

also aimed at the usefulness of measuring ScvO2 or SvO2 on ICU admission, we think these

factors are not pertinent to the results. For example, Bracht et al. [20] found no correlation

between ScvO2 values and length of hospital stay before unplanned ICU admission.

Comparing our sepsis population with the ED population described in the important

study by Rivers [8] is purely ment to be illustrative. Obviously, as we described, there are

differences between ED and ICU populations in general. But there are also, depending on

geographical setting, important differences between populations and health care systems.

And so, we subscribe to the view of Ho et al. [25] that the syndrome described in the EGDT

trial may be relatively uncommon depending on geographical setting and health care system.

However, this does not undermine the importance of early identification of patients at high

risk for cardiovascular collapse. For example, in our study of the fourteen patients with a

ScvO2 < 50% the in-hospital mortality was 57%.Finally, the in-hospital mortality in our study

was 32.0% for the total population and 27.0 % for the patients with severe sepsis or septic

shock. Again this reflects recent findings by others: Ho et al. (30.2%) [25] and Shapiro et al.

(26.9%) [26].

In conclusion, the incidence of low ScvO2 values on acutely admitted critically ill

patients is low in Dutch ICUs. This is especially true for patients with sepsis / septic shock.

Acknowledgments

The authors would like to thank research nurses Matty Koopmans and Vivian Leeuwe

for their invaluable help in the acquisition of patient data.

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Chapter 3

Relation between mixed venous and central

venous saturation in sepsis: no influence of

sepsis origin

Paul van Beest, Jan van Ingen, Christiaan Boerma,

Nicole Holman, Henk Groen, Matty Koopmans,

Peter Spronk, Michaël Kuiper

Abstract

Introduction We tested the hypothesis that central venous saturation (ScvO2) does not

reliably predict mixed venous saturation (SvO2) in sepsis. Additionally we looked at the

influence of the source (splanchnic or non-splanchnic) of sepsis on this relation.

Methods We concurrently determined ScvO2 and SvO2 in a group of 53 patients with severe

sepsis during the first 24 hours after admission to the intensive care units in 2 Dutch

hospitals. We assessed correlation and agreement of ScvO2 and SvO2., Additionally, we

compared the mean differences between ScvO2 and SvO2 of both splanchnic and non-

splanchnic group.

Study Design Prospective observational two-center study.

Results A total of 265 paired blood samples were obtained. ScvO2 overestimated SvO2 by

less than 5% with wide limits of agreement. For changes in ScvO2 and SvO2 results were

similar. The distribution of the difference (ScvO2 - SvO2) (< 0 or ≥ 0) was similar in survivors

and nonsurvivors. The mean (ScvO2 - SvO2) in the splanchnic group was similar to the mean

(ScvO2 - SvO2) in the non-splanchnic group (0.8 ± 3.9% vs. 2.5 ± 6.2 %; p = 0.30). Oxygen

extraction ratio (O2ER; p=0.23) and its predictive value for outcome (p=0.20) was similar in

both groups.

Conclusions ScvO2 does not reliably predict SvO2 in patients with severe sepsis. The trend

of ScvO2 is not superior to the absolute value in this context. A positive difference (ScvO2 -

SvO2) is not associated with improved outcome.

Introduction

Global tissue hypoxia as a result of systemic inflammatory response or circulatory

failure is an important indicator of serious illness preceding multiple organ failure. The

development of organ failure predicts outcome of the septic patient [1]. Unrecognized and

untreated global tissue hypoxia increases morbidity and mortality: decreased mixed venous

saturation (SvO2) values predict poor prognosis in septic shock [2-4].

Controversy however remains: there is no clear evidence that guiding hemodynamic

optimization by monitoring central venous saturation (ScvO2) or SvO2 is useful in all patients

with sepsis or septic shock, especially in intensive care unit (ICU) setting. The controversy

includes their interchangeability [5,6].

Also, in patients with a splanchnic cause of sepsis, ScvO2 may be normal, while the

SvO2 may be decreased due to elevated metabolic demand. On the other hand, due to

sepsis related vasodilatation, also in the digestive tract, leading to diminished oxygen

consumption, mixed venous saturation may be normal [7]. This could mean that the 5%

difference between ScvO2 and SvO2 is not as consistent in sepsis as postulated earlier [8,9].

Nevertheless, recently an association between a positive gradient O2 gradient (ScvO2 – SvO2

≥ 0) and ICU survival in critically ill patients was described [10]. Therapy aimed at increasing

this gradient is could mean improved survival. However, this demands measurement of both

ScvO2 and SvO2.

We tested the hypothesis that ScvO2 does not reliably predict SvO2 in sepsis, i.e. a

consistent 5% difference between ScvO2 and SvO2 does not exist. We also looked at the

possible relationship between a positive difference between ScvO2 and SvO2 (ScvO2 - SvO2)

and ICU survival. In a secondary analysis we tested the hypothesis whether the relationship

between ScvO2 and SvO2 is independent of sepsis origin or not.

Methods

Setting

We studied ICU populations in two teaching hospitals. The Martini Hospital

[Groningen, The Netherlands] (MH) where the ICU is a 14-bed “closed format” mixed medical

/ surgical ICU department and The Medical Center Leeuwarden [Leeuwarden, The

Netherlands] (MCL) where the ICU is a 16-bed “closed format” mixed medical / surgical ICU,

including cardiothoracic patients. The study was approved by both Local Ethics Committees.

Informed consent was obtained in all cases from the patient or from the patient’s legal

representative.


This prospective observational study included patients, all 18 years or older, with

sepsis or septic shock according to international criteria [11], between January and

September 2009. Only patients were included in whom there was a clinical indication for

additional hemodynamic monitoring using a pulmonary artery catheter (PAC) [Criticath SP

5507H TD, Becton Dickinson, Singapore] or a Continuous Cardiac Output (CCO) catheter

[Arrow Deutschland GmbH, Erding, Germany]. The catheter was inserted into an internal

jugular vein or subclavian vein according to standard procedure. Position was confirmed by

the presence of pulmonary artery pressure tracings and chest radiography. No complications

other than transient arrhythmias were observed during the insertion of any catheter. Primary

data, including hemodynamic parameters, were collected at 6-hour interval (T0, T1, T2, T3,

T4) during the first 24 hours after acute ICU admission. Standard blood samples of 2 ml were

drawn simultaneously from distal (pulmonary artery; PA) and proximal / side portal (superior

caval vein; SCV) from PAC or CCO catheter. To avoid falsely high readings due to aspiration

of pulmonary capillary blood, aspiration was done gently to avoid high negative pressure

when blood samples were taken. We took blood from the proximal port of the catheter as

representative of central venous blood [6,8,10]. We did not use any continuously measured

values of the catheter itself in the cases where a CCO catheter was used. Only patients with

a complete series of 5 paired measurements were finally included. Also, arterial blood

samples were obtained, including serum lactate. All blood samples were analyzed by a co-

oximeter (Radiometer ABL800 flex, Copenhagen, Denmark). The Acute Physiology, Age and

Chronic Health Evaluation (APACHE) II-score after 24 hours of ICU admission was collected

[12].


Analysis was done for the total population and for secondary analysis the population

was divided into two groups: patients with splanchnic source of sepsis and patients with a

non-splanchnic source of sepsis. We calculated a sample size of 200 paired samples to

detect an absolute difference between ScvO2 and SvO2 in a two-sided test with a 0.05 type I

error and a 95% probability in case of standard deviation of 10% [13,14]. Statistical tests

were two-tailed and performed by the statistical package for the social sciences (SPSS

16.0.1 for Windows, Chicago, IL, USA) or MedCalc software (version 11.2.1, Mariakerke,

Belgium), the latter for comparing ROC curves. GraphPad software (Prism 5.0, La Jolla, CA,

USA) was used for graphics. Measurements were not independent but clustered within each

patient. All data were tested for normal distribution with the Kolmogorov-Smirnov test before

further statistical analysis. Differences between both groups were assessed using Student’s

t-test in case of normal distribution or χ2 test. For each time point, T0 toT4, (ScvO2 - SvO2)

was calculated including the average difference per patient. The agreement between

absolute values of ScvO2 and SvO2 and the agreement of the changes of these values were

assessed by the mean bias and 95% limits of agreement (mean bias ± 1.96 x standard

deviation) as described by Bland and Altman [15]. χ2 test was used to establish significance

between the number of survivors and non-survivors. Spearman correlations for assessing

possible factors affecting (ScvO2 - SvO2) were determined: at each time point (ScvO2 - SvO2)

was compared to hemodynamic and perfusion variables.

For secondary analysis we also calculated the mean (ScvO2 - SvO2) per group and

they were compared using Student’s unpaired t-test. Additionally, the influence on outcome

of O2ER was determined because (ScvO2 - SvO2) did correlate with O2ER in the secondary

analysis. SvO2 and arterial oxygen saturation (SaO2) were used in the calculation of the

systemic oxygen extraction ratio (O2ER). Receiver Operating Characteristic (ROC) curves

were used for the assessment of sensitivity and specificity of O2ER in predicting in-hospital

mortality. Data were displayed as mean ± SD. Statistical significance was assumed at p <

0.05.

Results

We enrolled 56 patients, of whom three patients were excluded due to lack of data

(technical problems). We evaluated data from 53 patients with sepsis. Altogether 265 paired

blood samples were obtained. Baseline characteristics and outcome of the total population

and both groups are shown in table 1. Length of stay at the ICU (LOSICU) was 12 ± 10 days

and length of stay at the hospital (LOSHOSP) was 25 ± 18 days.

Table 1. Baseline characteristics and outcome

variable total population

(n=53)

splanchnic

(n=25)

non-splanchnic

(n=28)

P value#

age (yr) 66 ±12 66 ± 12 66 ± 13 0.46

CVP (mmHg) 12 ± 6 11 ± 5 14 ± 6 0.06

MAP (mmHg) 66± 10 65± 12 66 ± 9 0.65

ScvO2 (%) 72.0 ± 10.0 73.7 ± 10.5 70.6 ± 9.6 0.29

SvO2 (%) 71.8± 10.6 75.2± 9.9 68.6 ± 10.5 0.03*

lactate (mmol/L) 3.5 ± 3.5 3.8± 3.8 3.5 ± 3.2 0.33

arterial pH 7.30± 0.10 7.29 ± 0.10 7.29 ± 0.12 0.43

hematocrit (%) 30.1± 5.7 30.2 ± 6.1 32.1 ± 5.7 0.59

APACHE II 26.6 ± 7.6 25.3 ± 7.3 28.7 ± 7.8 0.24

hospital mortality (%) 26.5 29.2 24.0 0.56

Data are presented as means ± SD or as numbers. # splanchnic group vs. non-splanchnic group.

CVP, central venous pressure; MAP, mean arterial pressure; ScvO2, central venous oxygen

saturation; SvO2, mixed venous oxygen saturation; APACHE II, acute physiology, age and

chronic health evaluation; * statistically significant difference

The ScvO2 overestimated the SvO2 by a mean bias (or absolute difference) of 1.7% ±

7.1% in the total population. The 95% limits of agreement were wide (-12.1% to 15.5%;

Figure 1A). Figure 2 illustrates this: mean ScvO2 and mean SvO2 values are shown at each

time point. Results at time point T=0 and at different time points were similar, including wide

limits of agreement (data and plots not shown). Bias between changes of ScvO2 and SvO2

was 0.6% ± 7.1% in the total population with 95% limits of agreement of -13.4% to 14.6%;

Figure 1B. Results were similar at time point T=0 and at different time points, including wide

limits of agreement (data and plots not shown).

40 60 80 100-20

-10

0

10

20A.

(ScvO2 + SvO2) / 2

Sc

vO

2 -

Sv

O2

-20 -10 0 10 20

-20

0

20

B.

(ScvO2 + SvO2) / 2

S

cv

O2 -

S

vO

2

Figure 1. Bland and Altman plot showing the agreement between A. ScvO2

and SvO2 (bias 1.7, 95% limits of agreement from -12.1 to 15.5) and in B.

changes in ScvO2 and SvO2 (bias 0.6, 95% limits of agreement from -13.4

to 14.6).

60

70

80

90

T=0 T=1 T=2 T=3 T=4

SvO2

ScvO2

ve

no

us

sa

tura

tio

n (

%)

Figure 2. Mean SvO2 and ScvO2 values at different time points. ScvO2 is

consistently higher than SvO2 without statistical difference (paired t-test;

all p > 0.05).

Differences between survivors and nonsurvivors

As ScvO2 of 70% has been used as a target for guided therapy in septic patients [4],

we evaluated the frequencies of ScvO2 values below 70% in both survivors and

nonsurvivors. Of all ScvO2 measurements in survivors 15% fell below 70%, whereas in

nonsurvivors 47% of all ScvO2 measurements fell below 70% (p < 0.01).

Assuming a 5% difference between ScvO2 and SvO2 [1], we also evaluated the

frequencies of SvO2 values below 65% in both survivors and nonsurvivors. Of all

measurements in survivors 7% fell below 65%, whereas in nonsurvivors 27% of all SvO2

measurements fell below 65% (p < 0.01).

0

50

100

150 A. total population

survivors nonsurvivors

No

. o

f m

easu

rem

en

ts

0

20

40

60


B. splanchnic

No

. o

f m

easu

rem

en

ts

0

20

40

60

80


C. non-splanchnic

No

. o

f m

easu

rem

en

ts

Figure 3. Number of paired measurements resulting in either a

(ScvO2 – SvO2) ≥0 (black bars) or in a (ScvO2 – SvO2) <0

(white bars). There was no significant different distribution of

(ScvO2 – SvO2) between survivors and non-survivors.

Figure 3 shows the number of paired measurements resulting in either a (ScvO2 -

SvO2)≥0 or in a (ScvO2 - SvO2) <0. There was no significant different distribution of (ScvO2 -

SvO2) between survivors and non-survivors in the total population (p=0.13), splanchnic group

(p=0.23) or non-splanchnic group (p=0.13).

Influence on difference between ScvO2 and SvO2 (ScvO2 – SvO2)

The difference between ScvO2 and SvO2 was dependent on the level of ScvO2 when

values of <60%, 60-70%, 70-80% and >80% were analyzed separately. The mean (ScvO2 -

SvO2) were 8.9%, 1.0%, 2.4%, and 4.2%, respectively. Due to low incidence (4.9%) of low

ScvO2 values (< 60%) we did not assess statistics on these differences. Assessment of

Spearman correlation coefficients did not show any relation between cardiac output (CO),

cardiac index (CI), dopamine (μg/kg/min), norepinephrine (μg/kg/min), mean arterial blood

pressure, arterial saturation, hemoglobin, hematocrit, pH, or lactate levels and (ScvO2 -

SvO2) (all p > 0.05). O2ER correlated significantly with (ScvO2 - SvO2) at all time points (all p

< 0.01).

Differences between groups

Secondary analysis showed that twenty-five patients presented with splanchnic

source of sepsis and 28 patients presented with a non-splanchnic source of sepsis. Thirty

patients (15 splanchnic / 15 non-splanchnic) were enrolled in the MCL and 23 (10 splanchnic

/ 13 non-splanchnic) patients were enrolled in the MH.

The sources of sepsis in the non-splanchnic group were mainly pneumonia (n = 16;

57%) and infection of the urogenital tract (n = 5; 18%). Other sources were meningitis,

arthritis, epiglottitis, endocarditis, and infected soft tissue.

At baseline, SvO2 (75.2 ± 9.9% vs. 68.6 ± 10.5%; p = 0.03) was different between

groups. There was no significant difference between the mean (ScvO2 - SvO2) of both

groups: splanchnic, 0.8 ± 3.9% vs. non-splanchnic, 2.5 ± 6.2 % (p = 0.30).

Bias between ScvO2 and SvO2 was 0.7% ± 6.3% (95% limits of agreement of -11.7%

to 13.1%) in the splanchnic group and 2.6% ± 7.5% (95% limits of agreement of -12.2% to

17.4%) in the non-splanchnic group. Bias between changes in ScvO2 and SvO2 was 0.9% ±

7.9% (95% limits of agreement of -14.5% to 16.3%) in the splanchnic group and 0.3% ± 6.5%

(95% limits of agreement of -12.4% to 13.0%) in the non-splanchnic group; plots not shown.

The difference between ScvO2 and SvO2 was dependent on the level of ScvO2 when

values of <60%, 60-70%, 70-80% and >80% were analyzed separately. The mean (ScvO2 -

SvO2) were 12.3%, 2.1%, 1.0%, 4.3% for the splanchnic group; 4.6%, 0.1%, 3.8%, and 4.7%

for the non-splanchnic group.

There was no significant different distribution of (ScvO2 - SvO2) between survivors

and non-survivors in both the splanchnic group (p=0.23) and the non-splanchnic group

(p=0.13); Figure 4.

Oxygen extraction ratio (O2ER)

The O2ER in the splanchnic group was similar to the O2ER in the non-splanchnic

group (0.23 ± 0.07 vs 0.24 ± 0.09; p=0.23). Figure 4 shows the ROC curves of O2ER for the

splanchnic and non-splanchnic group. Optimal value of O2ER was 0.22 (sensitivity = 0.46,

specificity = 0.87) for the non-splanchnic group and 0.31 (sensitivity = 0.85, specificity 0.40)

for the splanchnic group. These curves represent the reliability of the O2ER as predictor of

in-hospital mortality. Area under the curve (AUC) in the splanchnic group was not

significantly larger than the AUC in the non-splanchnic group (0.67 vs. 0.55; p=0.20).

Figure 4. ROC curves of O2ER for the splanchnic

and non-splanchnic group. AUC in the splanchnic

group (A) was not significantly larger than AUC in

the non-splanchnic group (B) (0.67 vs. 0.55;

p=0.20).

Discussion

We could confirm our hypothesis that ScvO2 does not reliably predict SvO2 in patients

with severe sepsis: the agreement of ScvO2 and SvO2 was clinically not adequate. The

difference between ScvO2 and SvO2 varied according to the level of ScvO2, being the

greatest in low (<60%) and high ranges (>80%). In patients with severe sepsis or septic

shock the difference between ScvO2 and SvO2 appears not to be a fixed one and does not

seem to be predictive for in-hospital mortality. Finally, the difference between ScvO2 and

SvO2 is independent of several hemodynamic variables, with exception of O2ER.

The bias was small with ScvO2 being consistently larger than SvO2. However, this

consistent bias also implies a greater relative error for SvO2 values at lower ScvO2 values.

Additionally, the wide limits of agreement between ScvO2 and SvO2 are unacceptably wide

and independent of time point. The widely assumed 5% difference between ScvO2 and SvO2

[1,8,9] seems not consistent in patients with severe sepsis or septic shock. A variety of

factors influence the difference between both variables in patients with sepsis: mixing of the

less saturated blood from the coronary sinus in the right atrium, sepsis related vasodilatation,

heterogeneity of flow within and between organs, and decreased cerebral oxygen uptake

during sedation. Based on the present study, the net effect of these factors seems

unpredictable. Our results seem concordant with earlier findings [6,8,16]. The first study

described a small heterogeneous group of patients with septic shock. ScvO2 was consistently

higher than SvO2 and the limits of agreement were equally wide. Moreover, the difference

between ScvO2 and SvO2 varied according to the level of ScvO2 and deviated in the extreme

ranges (60% < ScvO2 > 80%) [6]. The lower range (venous saturations < 60%) is clinically of

the greatest interest because the patients admitted with such low venous saturations are the

ones who could possibly benefit from ScvO2 -guided therapy [4]. With the results of the

present study in mind the clinician should be aware of the large variability between ScvO2

and SvO2. Clinically important, this large variability was already present on admission (T=0).

At this time point the first decisions are made on how to resuscitate and on what goals

should be achieved. Such large uncertainty in estimating SvO2 by ScvO2 is unlikely to be

suitable for protocol-guided resuscitation in which decreases in SvO2 or ScvO2 may trigger

therapeutic interventions. Normalization of ScvO2 after resuscitation will not automatically

imply normalization of SvO2.

If the individual values of ScvO2 and SvO2 do not agree could this be different for the

trends of ScvO2 and SvO2? In anesthetized subjects who underwent elective neurosurgery

measurement of oxygen saturations was performed in various hemodynamic conditions. It

was concluded that for clinical purposes the trend of ScvO2 might be substituted for the trend

of SvO2 [17]. In the present study however, we found wide limits of agreement between the

change of ScvO2 and the change of SvO2 in critically patients. As for the absolute values of

ScvO2 and SvO2, substitution of the change of ScvO2 for the change of SvO2 in patients with

sepsis is therefore undesirable. This is in concordance with earlier findings in patients with

cardiogenic or septic shock: changes in ScvO2 and SvO2 did not follow the line of perfect

agreement and ScvO2 and SvO2 were not considered to be interchangeable [18].

Another issue is whether a ScvO2 of 70% as treatment goal in sepsis or septic shock

after resuscitation may be considered useful. In a study by Reinhart et al. ScvO2 was

measured continuously in critically ill patients for an average of 42 hours. More than 87% of

the values in nonsurvivors and 95% of the values in survivors were above 70%. This

difference was significant. Average time per patient below the cutoff value was twice as long

in nonsurvivors [5]. In the present study ScvO2 values in nonsurvivors fell also more

frequently below the cutoff value of 70% compared to survivors and SvO2 values below 65%

were more frequently found in nonsurvivors compared to survivors. Our data suggest that

after the first hours of resuscitation monitoring of venous oxygen saturations could still be

clinically relevant.

More recently, Gutierrez et al. described an association between a positive (ScvO2 –

SvO2), and ICU survival in critically ill patients. A significantly greater number of survivors

had a (ScvO2 - SvO2) ≥0 compared to non-survivors. The difference between ScvO2 and

SvO2 became increasingly positive in survivors from initial to final measurement. They

suggested that this might be associated with clinical recovery, perhaps reflecting a greater

rate of O2 utilization [10]. This is in concordance with findings in post-operative cardiac

patients which described a similar trend [19]. Although we noted that (ScvO2 - SvO2) was

more frequently positive in survivors, and O2ER correlated with (ScvO2 - SvO2) we found no

significant difference in distribution of (ScvO2 - SvO2) between survivors and non-survivors.

Our results could not confirm a greater rate of O2 utilization in survivors as suggested by

Gutierrez et al [10]. However, it is possible that the number of measurements in our study

was not sufficient enough to detect a difference in distribution of (ScvO2 - SvO2).

Secondary analysis showed that the inconsistent difference between ScvO2 and SvO2

is independent of sepsis origin. There was no significant difference between the mean

(ScvO2 - SvO2) of both groups and the limits of agreement were wide for both the absolute

values and for the changes in ScvO2 and SvO2. SvO2 values were higher in the splanchnic

group compared to the non-splanchnic group for a certain ScvO2 value. This phenomenon

could be explained by sepsis related vasodilatation in the digestive tract. Despite

heterogeneity of flow within and between various organs in patients with splanchnic sepsis

[20] this leads to diminished oxygen consumption which results in a relatively higher SvO2.

Apparently, a normal SvO2 does not rule out the presence of limited oxygen consumption in

the splanchnic region [7]. Moreover, we found no difference in O2ER between the splanchnic

and non-splanchnic group. This suggests less oxygen utilization in the digestive tract than

could be expected based on the assumption that in all septic patients the difference between

ScvO2 and SvO2 equals 5%.

This study has limitations. First, all patients were sedated, mechanically ventilated,

and none of them were in hemorrhagic shock. Our findings may not be generalized to

patients less critically ill or those with hemorrhagic shock. Also, due to intubation ScvO2

values could have been relatively high in relation to disease severity [21]. Second, we

investigated ICU patients which could mean at a later stage of sepsis; timing of

measurements was probably not all in the same stage of critical illness. Third, in this study

ScvO2 and SvO2 values did not change between different time points as a result of a

protocolled intervention: conclusions on independence of time point are of limited value.

However, measurements took place within individual patients: each subject served as its own

control. Finally, we used the proximal port of the used catheters as surrogate of ScvO2.

Some ScvO2 measurements might have been influenced due to a more distal location in the

right atrium which allows mixing of superior and inferior caval vein blood. Nevertheless, our

results are consistent and in concordance with previous studies where a similar technique

was used [6,8,10].

Conclusions

We conclude that ScvO2 does not reliably predict SvO2 in patients with sepsis,

independent of sepsis origin. Assuming a consistent 5% difference between ScvO2 and SvO2

can lead to erroneous clinical decisions. The change of ScvO2 compared to the change of

SvO2 is not more reliable than the exact numerical values in this context. Finally, a positive

difference (ScvO2 - SvO2) is not associated with improved outcome in patients with sepsis.

The abovementioned conclusions apply for sepsis originated from both splanchnic and non-

splanchnic origin.

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doi:10.1053/j.jvca.2007.10.011.


C: Agreement of central venous saturation and mixed venous saturation in cardiac

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Chapter 4

Femoral venous oxygen saturation is no

surrogate for central venous oxygen saturation

Paul van Beest, Alice van der Schors,

Henriëtte Liefers, Ludo Coenen, Richard Braam,

Najib Habib, Annemarije Braber,

Thomas Scheeren, Michaël Kuiper,

Peter Spronk

Abstract

Objective The purpose of our study was to determine if central venous oxygen saturation

(ScvO2) and femoral venous oxygen saturation (SfvO2) can be used interchangeably during

surgery and in critically ill patients.

Methods We concurrently determined SfvO2 and ScvO2 in a group of 100 stable cardiac

patients, which served as control group. Furthermore, we determined simultaneously SfvO2

and ScvO2 in 30 surgical patients and in 30 critically ill patients and evaluated changes over

time. Correlation and agreement of SfvO2 and ScvO2 were assessed, including the difference

between SfvO2 and ScvO2.

Results Despite significant correlation between obtained values of SfvO2 and ScvO2 (rs =

0.55; p < 0.001), the limits of agreement (LOA) were wide in the control group (mean bias

2.7% ± 7.9%; 95% LOA: -12.9 to 18.2%). In both the surgical and critically ill patients, LOA

(mean bias of -1.9% ± 9.3%; 95% LOA: -20.0% to 16.3%, and mean bias of 4.6% ± 14.3%;

95% LOA: -23.5% to 32.6%, respectively) were wide. Results for changes of SfvO2 and

ScvO2 were similar. During initial treatment of critically ill patients, the difference between

SfvO2 and ScvO2, including its range of variation diminished.

Conclusion There is lack of agreement between SfvO2 and ScvO2 in both stable and

unstable medical conditions. Thus, SfvO2 should not be used as surrogate for ScvO2.

Introduction


systemic oxygen delivery (DO2) and oxygen demand (VO2). Unrecognized and untreated

global tissue hypoxia increases morbidity and mortality [1-3]. Measurement of mixed venous

oxygen saturation (SvO2) from the pulmonary artery (PA), i.e. the downstream site of the

circulation, has been advocated as an indirect index of tissue oxygenation [4]. Hence, SvO2

reflects the balance between oxygen delivery and demand [5]. The normal range for SvO2 is

65 to 75% [4,6] and low SvO2 is predictive of bad outcome [4,7]. However, PA catheterization

is costly and obtaining the first SvO2 values may be relatively time consuming. As a result of

these disadvantages and an international debate on the use of PA catheter [8-10] its use has

become, justifiable or not [11], somewhat unpopular.

Just as SvO2, the measurement of central venous oxygen saturation (ScvO2) has

been described to detect global tissue hypoxia. Early goal-oriented manipulation of cardiac

preload, afterload and contractility, to restore the balance between systemic oxygen delivery

and oxygen demand has been shown to improve outcome [12]. Although there has been

considerable debate on equality or interchangeability of ScvO2 and SvO2, ScvO2 has been

used as a therapeutic goal in resuscitation protocols as a surrogate marker for SvO2 [13].

To monitor ScvO2, insertion of a central venous catheter in the superior vena cava via

the jugular or subclavian vein is required. However, sometimes the femoral vein is the

preferred (inexperienced hands) or only possible (trauma; previous attempts failed) site for

access in acutely ill patients. As shown in a recent survey, femoral catheters are commonly

used during the first hours of treatment of critically ill patients [14]. Apart from possible

disadvantages compared to jugular or subclavian portal such as arterial puncture and

thrombosis [15], the use of femoral catheters has several advantages. Femoral access is

quick, relatively safe and radiographic control is not required [16] because there is no risk for

pneumothorax. Hence, the femoral venous access can be very useful in the care of acutely ill

patients.

There is little information on the relevance of SfvO2 [14,17,18]. The purpose of our

study is first to determine if ScvO2 and femoral venous oxygen saturation (SfvO2) can be

used interchangeably in critically ill patients and in high-risk surgery and second, to evaluate

whether changes in SfvO2 may be used as a parameter for treatment.

Methods

Study centre

This prospective, observational, controlled study was performed in a non-academic

university affiliated teaching hospital in The Netherlands [Gelre Hospital location Lukas in

Apeldoorn, The Netherlands]. The ICU is a 12-bed “closed format” department. Per year

about 17,500 surgical procedures are performed in this hospital. The study was approved by

the Local Ethics Committee. Written informed consent was obtained in all cases from the

patient or from the patient’s legal representative.


Three groups of patients were analyzed. First, 100 stable cardiac outpatients who

underwent elective right heart catheterization in day care. This population served as control

group. Second, 30 high-risk (ASA score > 2) patients who underwent elective intermediate /

high-risk surgery (surgical patients). Third, 30 consecutive critically ill patients who were

acutely admitted to the ICU either directly from the ED, from the general ward or after acute

surgery with septic shock [19] or cardiogenic shock [20] (ICU patients).

All included patients were older than 18 years. Exclusion criteria were acute

abdominal or thoracic aneurysm, pregnancy, lack of data (technical problems) or lack of

written informed consent.

In the control group not only ScvO2 and SfvO2, but also SvO2 was determined. During

the right heart catheterizations 3 samples (femoral vein, proximal inferior caval vein,

pulmonary artery) were obtained after routine cannulation of the femoral vein. Correct

position of the catheter was confirmed by real-time angiography.

In the surgical patients samples were obtained simultaneously before start of the

procedure, i.e. after induction but before application of sterile sheeting (T=0), and at the end

of the procedure, i.e. after sterile sheeting was removed (T=1). In the ICU patients samples

were simultaneously obtained in the first hour of resuscitation (T=0) as soon as the central

venous line was in place, and 6 hours thereafter (T=1). Femoral blood samples were

obtained by puncture.

In the surgical and ICU patients hemodynamic measurements as well as blood

samples and arterial blood gas analyses were recorded. Also, the use of fluids, packed red

blood cells and vasopressors were recorded.

Central venous catheters [Edwards Lifesciences LLC, Irvine, CA, USA; usable length

16 cm.] were inserted into an internal jugular vein or subclavian vein according to standard

procedure. Correct position in the superior caval vein was confirmed by the presence of

central venous pressure tracings and chest radiography. No complications other than

transient arrhythmias were observed during the insertion of any catheter. In case of the use

of a pulmonary artery catheter (PAC) [Criticath SP 5507H TD, Becton Dickinson, Singapore]

in the ICU, blood samples were drawn from the proximal port of the catheter as

representative of central venous blood [21-23]. All blood samples were analyzed by a co-

oximeter (Radiometer ABL800 flex, Copenhagen, Denmark). The Acute Physiology, Age and

Chronic Health Evaluation (APACHE) II-score was collected for ICU patients [24].


Statistical tests were two-tailed and performed by the statistical package for the social

sciences (IBM SPSS 19 for Windows, Chicago, IL, USA). GraphPad software (Prism 5,

version 5.02 for Windows, and StatMate 2.0, San Diego, CA, USA) was used for graphics.

Measurements were not independent but clustered within each patient. All data were tested

for normal distribution with the D’Agostino-Pearson omnibus normality test before further

statistical analysis. T-test (paired) was used where appropriate. Non-parametric testing of

continuous variables was performed using Mann-Whitney-U test or Wilcoxon’s paired rank-

sum test. Otherwise the Fisher’s exact test was used. For both time points (T=0 and T=1) in

the surgical and ICU group, (SfvO2 - ScvO2) was calculated.

Paired samples were compared by (Spearman, rs) correlation [25] and the agreement

between absolute values of ScvO2 and SfvO2 and the agreement of the changes of these

values were assessed by the mean bias and 95% limits of agreement (mean bias ± 1.96 x

standard deviation (SD)) as described by Bland and Altman (BA analysis) [26]. Limits of

agreement (LOA) were considered acceptable if they were within 5%. Based on the findings

in the control group (SD 7 to 10; r = 0.60) we determined that number of paired samples

required for a 90% power in a two-sided test with a 0.05 type I error would be 30. Data are

displayed as median [interquartile range (IQR)]. Statistical significance was assumed at p <

0.05.

Results

Control group

In 100 patients (46 males, 54 females) who underwent elective right heart

catheterization we obtained 100 paired blood samples. Median age was 73 [63 - 80] years.

SvO2 and ScvO2 correlated significantly (p < 0.001) with rs = 0.85. BA analysis

revealed a bias (or absolute difference) of 0.5% ± 2.8% (95% LOA of -4.8 to 5.9%).

Median SfvO2 was lower than median SvO2 (66.3 [58.1 - 73.0]% vs. 68.9 [64.3 –

72.6]%; p=0.03). According to BA analysis the mean bias between SvO2 and SfvO2 was

2.1% ± 7.9%; 95% LOA -13.0 to 17.5%. Correlation between SvO2 and SfvO2 was significant

(rs = 0.57; p < 0.001).

Results for median SfvO2 and median ScvO2 were very similar. Median SfvO2 was

lower than ScvO2 (66.3 [58.1 - 73.0]% vs. 69.2 [64.9 - 73.2]%; p < 0.01) According to BA

analysis the bias between ScvO2 and SfvO2 was 2.7% ± 7.9% 95% LOA were -12.9 to 18.2%

(figure 1). Fifty-five percent of the paired SfvO2 and ScvO2 samples diverged by > 5%.

Nevertheless, ScvO2 correlated with SfvO2 (rs = 0.55; p < 0.001).

50 60 70 80 90 100

-40

-20

0

20

40control group

(ScvO2 + SfvO2) / 2

ScvO

2 -

Sfv

O2

Figure 1. Control Group. Bland and Altman plot showing the

agreement between ScvO2 and SfvO2 (bias 2.7%, 95% LOA

from -12.9% to 18.2%).

Surgery group

Altogether 60 paired blood samples were obtained in 30 patients. Baseline

characteristics are shown in table 1. Co-morbidities in this group of surgical patients: arterial

hypertension (20), cardiac (atrial fibrillation, coronary artery disease) (12), diabetes mellitus

(9), chronic obstructive pulmonary disease (6), neurological (6), other (21).

Table 1. Characteristics of surgical and ICU patients

variable surgery

(n=30)

ICU

(n=30)

P value septic shock

(n=26)

age (yr)

75 [64 - 81]

75 [67- 80]

0.98

75 [67 - 82]

gender (male / female) 15 / 15 19 / 11 0.43 15/11

MAP (mmHg) 74 [66 - 81] 74 [63 - 90] 0.75 74 [61 - 90]

heart rate

(beats / minute)

73 [62 - 87] 109 [96 - 131] < 0.001 107 [96 - 114]

hematocrit (%) 30.0 [27.8 - 34.0] 33.5 [30.0 - 37.0] 0.05 32.0 [30.0 - 35.5]

FiO2 0.45 [0.40 - 0.50] 0.60 [0.40 - 0.65] 0.10 0.58 [0.40 - 0.60]

APACHE II 22 [17- 28] 24 [15 - 30]

CVC

(jugular / subclavian)

29 / 1 14 / 16 <0.001 12 / 14

ScvO2 (%) 81.0 [ 78.0 - 86.5] 77.0 [65.8 - 83.3] 0.02 78.0 [65.7 - 83.0]

SfvO2 (%) 83.0 [ 78.0 - 88.0] 71.0 [58.8 - 82.0] < 0.001 74.0 [63.5 - 81.2]

ICU, intensive care unit; MAP, mean arterial pressure; FiO2, fraction of inspired oxygen; APACHE II, acute

physiology, age and chronic health evaluation; CVC, central venous catheter; ScvO2, central venous oxygen

saturation; SfvO2, femoral venous oxygen saturation. Data are presented as median [IQR] or as numbers; P

value, ICU vs. surgery.

Types of surgery (and number) performed on these patients were as follows: liver (9),

lung (8), colon (6), aorta (4), and other (3). Median length of stay in the hospital (LOSHOSP)

was 10 [6-19] days. Post-operative complications included: pneumonia (4), ileus (4),

relaparotomy (4), cardiac ischemia (3), de novo atrial fibrillation (2), neurological (1), wound

infection (1), urinary tract infection (1), systemic inflammatory response syndrome (1),

pulmonary embolus (1), and other (5). None of the patients died postoperatively in the

hospital.

At T=0 the SfvO2 underestimated the ScvO2 (bias of -1.9% ± 9.3%). The 95% LOA

were -20.0% to 16.3% (figure 2). At T=1 the SfvO2 underestimated the ScvO2 (bias of -1.0%

± 14.9%). The 95% LOA ranged from -30.2% to 28.3% (figure 2). At both time points SfvO2

and ScvO2 did not correlate significantly (p = 0.23 and p = 0.06, respectively). The

differences between median (SfvO2 - ScvO2) at T=0 and T=1 were not significant (2.0 [-5.0 -

7.5]% vs. 4.0 [-6.5 - 7.0]%; p = 0.71). The median changes of SfvO2 and ScvO2 from T = 0 to

T = 1 were equivalent (-5.0 [-13.8 - 5.8]% vs. -2.0 [-11.0 - 2.5]%; p = 0.89). In only 57% the

changes in SfvO2 and ScvO2 over time were in the same direction; this was independent of

the type of surgery.

ICU group

Thirty acutely admitted patients were included. Baseline characteristics are shown in

table 1. At admission, four patients were in cardiogenic shock based on acute coronary

syndrome or cardiac failure. Twenty-six patients were in septic shock. Causes of sepsis were

respiratory (n=13), abdominal (n=8), urological (n=2), or other (n=3). In the majority of

patients (28/30) one or more inotropes were used (28/30): dopamine (n=1), norepinephrine

(n=16), milrinone (n=26), isoprenaline (n=1).

Figure 2. Bland and Altman plots showing the agreement between ScvO2 and SfvO2 in the

surgery group at T=0 and T=1 and in the ICU group at T=0 and T=1; various bias and 95% LOA

in results section.

At T=0 the SfvO2 overestimated the ScvO2 (bias of 4.6% ± 14.3%). The 95% LOA

were -23.5% to 32.6% (figure 2). At T=1 the SfvO2 overestimated the ScvO2 (bias of 3.3% ±

11.1%). The 95% LOA ranged from -18.5% to 25.1% (figure 2). At both time points SfvO2

and ScvO2 correlated significantly (p = 0.01 and p = 0.002, respectively) with comparable rs

(0.46 vs. 0.55). The difference between SfvO2 and ScvO2 and the range of variation

diminished over time (from -4.0 [range -44.0 to 28.0] at T=0 to -1.0 [range -32.0 to 11.0] at

T=1; figure 3).

-40

-20

0

20

40

T=1T=0

Sfv

O2 -

ScvO

2

Figure 3. ICU group. The median

difference between SfvO2 and ScvO2 at

T=0 (-4.0%, range -44% to 28%) and T=1

(-1.0%, range -32% to 11%).

Changes of SfvO2 and ScvO2 over time occurred in the same direction in 87% of the

cases (26/30; in-hospital mortality 27% (7/26)). In twenty of these patients the value of both

SfvO2 and ScvO2 increased; mortality of this subgroup was 25% (5/20). In four cases ScvO2

increased after treatment while SfvO2 decreased. In-hospital mortality in this small subgroup

(75% (3/4)) was not significantly higher compared to the other 26 patients (p=0.33). The 95%

LOA between both changes were -32.6% to 30.1%. The total in-hospital mortality in this

group was 33%.

Results for 26 patients in septic shock were similar to the results of the total ICU

group (table 1). At T=0 the SfvO2 overestimated the ScvO2 (bias of 2.2% ± 12.8%). The 95%

LOA were -27.5% to 22.8%. At T=1 the SfvO2 overestimated the ScvO2 (bias of 3.5% ±

11.9%). The 95% LOA ranged from -26.5% to 19.9%. At both time points SfvO2 and ScvO2

correlated significantly (p = 0.01 and p = 0.003, respectively) with comparable rs (0.43 vs.

0.54). Median LOSHOSP was 13 [5-27] days and in-hospital mortality was 35% (9/26).

Comparison between patient groups

Gender and age were equally distributed in the control and surgery group (table 2).

The absolute values of SfvO2 and ScvO2 were higher in the surgery group compared to the

control group (table 2). The difference between SfvO2 and ScvO2 values also varied

significantly between study groups (table 2).

Table 2. Comparison of study groups (T=0)

control

(n = 100)

surgery

(n=30)

P value a ICU

(n=30)

P value b

age (year)

gender (m / f)

ScvO2 (%)

SfvO2 (%)

SfvO2 - ScvO2 (%)

73 [63-80]

46 / 54

69.2 [64.9 - 73.2]

66.3 [58.1 - 73.0]

-1.5 [-8.5 - 2.7]

75 [64 - 81]

15 / 15

81.0 [ 78.0 - 86.5]

83.0 [ 78.0 - 88.0]

2.0 [-5.0 - 7.5]

0.39

0.83

<0.001

<0.001

0.03

75 [67-80]

19 / 11

77.0 [65.8 - 83.3]

71.0 [58.8 - 82.0]

-4.0 [-12.3 - 2.5]

0.41

0.14

<0.001

0.06

0.37

ICU, intensive care unit; m, male; f, female; ScvO2, central venous oxygen saturation; SfvO2, femoral venous

oxygen saturation; SfvO2 - ScvO2, difference between SfvO2 and ScvO2; a surgery vs. control group;

b ICU vs.

control group; Data are presented as median [IQR] or as numbers.

In contrast to the median value of SfvO2 median value of ScvO2 was higher in the

acutely admitted critically ill patients compared to the patients in the control group.

The absolute values of the venous oxygen saturations were significantly lower in the

septic ICU patients (ScvO2 77.0 [65.8 - 83.3]%; SfvO2 71.0 [58.8 - 82.0]%) than in surgical

patients (ScvO2 81.0 [78.0 - 86.5]%; SfvO2 83.0 [78.0 - 88.0]%) at T=0. This difference

disappeared at T=1 (table 3).

Table 3. Characteristics surgical and ICU patients at different time points

variable surgery

(n=30)

ICU

(n=30)

P value

T = 0

MAP (mmHg) 74 [66 - 81] 74 [63 - 90] 0.75

heart rate (beats / minute) 73 [62 - 87] 109 [96 - 131] < 0.001

ScvO2 (%) 81.0 [78.0 - 86.5] 77.0 [65.8 - 83.3] 0.02

SfvO2 (%) 83.0 [78.0 - 88.0] 71.0 [58.8 - 82.0] < 0.001

FiO2 0.45 [0.40 - 0.50] 0.60 [0.40 - 0.65] 0.10

SfvO2 - ScvO2 2.0 [-5.0 - 7.5] -4.0 [-12.3 - 2.5] 0.03

T = 1

MAP (mmHg) 77 [72 - 94] 65 [59 - 74] < 0.001

heart rate (beats / minute) 82 [66 - 99] 99 [84 - 109] 0.03

ScvO2 (%) 79.0 [72.8 - 83.0] 81.5 [75.0 - 83.3] 0.47

SfvO2 (%) 83.0 [71.5 - 87.0] 79.5 [72.0 - 85.0] 0.46

FiO2 0.45 [0.40 - 0.67] 0.45 [0.40 - 0.60] 0.53

SfvO2 - ScvO2 4.0 [-6.5 - 7.0] -1.0 [-6.8 - 4.3] 0.08

change of ScvO2 (T1 – T0) -2.0 [-11.0 - 2.5] 5.0 [ 1.0 - 10.3] 0.001

change of SfvO2 (T1 – T0) -5.0 [ -13.8 - 5.8] 4.5 [-4.8 - 21.0] 0.01

total infusion (ml) 3150 [ 1534 - 4795] 3286 [2369 - 5135] 0.43

fluid balance (ml) 272 [-525 - 1127] 2589 [1137 - 3721] 0.01

ICU, intensive care unit; MAP, mean arterial pressure; FiO2, fraction of inspired oxygen; APACHE

II, acute physiology, age and chronic health evaluation; CVC, central venous catheter; ScvO2,

central venous oxygen saturation; SfvO2, femoral venous oxygen saturation. Data are presented as

median [IQR] or as numbers.

Discussion

We conclude that SfvO2 should not be used as a surrogate of ScvO2 due to the lack

of agreement between both variables under different circumstances. This uncertainty in

estimating ScvO2 by SfvO2 hampers protocol-guided hemodynamic optimization in which

decreases in SfvO2 of ScvO2 may trigger therapeutic interventions. As for the absolute values

of SfvO2 and ScvO2, substituting the change of ScvO2 by the change of SfvO2 is not suitable.

These results are of confirmative but also additional value with respect to recent reports on

populations of critically ill patients [14, 17].

This is the first study describing the relationship between femoral and non-femoral

central venous saturations in outpatients. Although those patients do not resemble healthy

volunteers, the results will give us at least an idea of the physiological relationship between

femoral and non-femoral central venous saturations in stable hemodynamic conditions. In

these stable conditions without any reason for redistribution of blood flow, the median values

of ScvO2 or SvO2 and SfvO2 were significantly different, and LOA as described by BA

analysis were wide. Apparently, even in stable hemodynamic conditions a statement on the

systemic balance between oxygen delivery and oxygen demand should not be based on

SfvO2 values.

No study compared ScvO2 and SfvO2 in surgical patients before. In the present study

mean biases between ScvO2 and SfvO2 were relatively small during anesthesia in

intermediate and high-risk surgery but LOA were wide. The Bland and Altman projections

implacably demonstrate that several values differed even more than 15% from each other.

Even more concerning was the lack of predictability for the direction of change of ScvO2 by

SfvO2: it’s like tossing a coin. We think that peri-operative protocols as suggested for ScvO2

[27,28] should not be based on SfvO2 values.

Treatment of shock implies improvement of the circulatory state with redistribution of

flow not only in vital organs but also in more peripheral tissue, including limbs. The results in

the ICU group elegantly show that after 6 hours of intensive treatment the mean difference

between SfvO2 and ScvO2 decreased, i.e. after reversal of shock and improvement of the

circulation SfvO2 approached ScvO2. In the vast majority of patients changes of SfvO2 and

ScvO2 occurred in the same direction, i.e. rise or fall, during resuscitation. Although not

significant due to insufficient power, the mortality rate was higher when ScvO2 increased but

SfvO2 decreased after 6 hours of treatment in the ICU (3/4; 75%). Apparently, in these cases

treatment failed to improve circulation and shock was not adequately reversed. Also, regional

(splanchnic, leg blood flow) changes in oxygen delivery and consumption cannot predict

systemic changes [28] and differences in regional oxygen extraction ratio [29] attribute to the

differences between ScvO2 and SfvO2 in our study. In conclusion, SfvO2 did not adequately

predict ScvO2 in critically ill patients. This is in line with recent clinical work in which a similar

lack of agreement between SfvO2 and ScvO2 was described [14,17]. Both studies describe

wide LOA as well, i.e. more than 50% of ScvO2 and SfvO2 values diverged by more than 5%

[14,17]. Although in those studies more critically ill patients (n=39 and n=43, respectively)

were included than in the present study, our study carries a control group and compares

changes of both values over time.

Several strengths of this study should be mentioned. First, a relatively large group of

stable cardiac patients served as control group. Second, a power analysis was performed

before the start of the study. Third, we did not only compare absolute values but also

changes over time of both ScvO2 and SfvO2 during treatment in surgery and in the ICU.

Fourth, femoral blood samples were taken by puncture, which excludes possible influences

of the catheter length on oxygen content or reliability of the samples.

However, this study also has limitations. First, measurements were done intermittently

and not continuously. Second, all surgical and ICU patients were sedated, mechanically

ventilated, and none of them were primarily in hemorrhagic shock. Therefore care must be

taken before generalizing our results to other patients with different pathophysiology. Third,

we investigated acutely admitted ICU patients and timing of measurements was probably not

always in the same stage of disease. However, this approach reflects common clinical

practice and is a well-known drawback in all studies involving critically ill patients. Fourth,

one may argue that movements of the legs, especially during global hypoxia may have

influenced the results. However, all cardiac patients were stable, locally anaesthetized and

lying still during the procedure. All surgical and most (28 out of 30) ICU patients were

measured after induction of general anesthesia. The other two ICU patients were quiescent

at the time of measurements. Furthermore, the occurrence of strong leg movements would

have caused even larger differences between ScvO2 and femoral venous saturations than

reported in our results. Hence, we do not think this potential confounder plays a role in our

study. Finally, in this study ScvO2 and SfvO2 values did not change between different time

points as a result of a study intervention. However, measurements took place within

individual patients: each subject served as its own control.

Conclusion

SfvO2 cannot replace ScvO2, neither in stable conditions nor during surgery or during the

resuscitation phase in critically ill patients.

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Chapter 5

Measurement of lactate in a prehospital setting

is related to outcome

Paul van Beest, Peter Jan Mulder,

Bambang Oetomo Suparto, Bert van den Broek,

Michaël Kuiper, Peter Spronk

Abstract

Objective We evaluated the relationship of lactate measured in a pre-clinical setting to

outcome. Simultaneously, we evaluated the feasibility of implementing blood lactate

measurement in a pre-hospital setting as part of a quality improvement project.

Methods Chart review of patients from whom serum lactate levels prospectively were

obtained in a pre-hospital setting. Total population was divided into two groups, i.e. a shock

group and a non-shock group according to predefined shock symptoms. The shock group

was divided into two groups, i.e. a lactate < 4mmol/L (subgroup I) and a lactate ≥ 4mmol/L

(subgroup II).

Results In about 50% of possible cases lactate was measured in the pre-hospital setting.

Median lactate in subgroup I (n=74) was 3.2 (1.5-3.9) mmol/L vs. 5.0 (4.0-20.0) mmol / L in

subgroup II (n=61) (p < 0.0001). Significant differences were found in length of stay in

intensive care unit (p = 0.03) or hospital (p = 0.04) and mortality (subgroup I 12.2% vs.

subgroup II 44.3%; p = 0.002). In normotensive shock patients revealing a lactate ≥ 4mmol/L

(n=27) the mortality was higher compared to normotensive shock patients with a lactate <

4mmol/L (n=31) (35% vs. 7%; p < 0.001).

Conclusion Implementation of lactate measurement in pre-hospital setting is feasible, and

potentially clinical relevant. Lactate measured in a pre-clinical setting is related to outcome.

Subsequent studies should evaluate if treatment of shock patients based on pre-hospital

lactate measurement will improve outcome.

Introduction

Physical findings and vital signs are important, but not always sufficient for accurate

detection of global tissue hypoxia [1]. Global tissue hypoxia as a result from systemic

inflammatory response or circulatory failure is an important indicator of shock preceding

multiple organ dysfunction syndrome (MODS). Due to global tissue hypoxia, with

concomitant risk of developing an oxygen debt, anaerobic metabolism occurs and lactate

production is increased. If this situation persists, the lactate metabolic clearance rate is

surpassed and circulating lactate levels may be elevated as well.

Numerous studies have established the use of lactate as a diagnostic, therapeutic

and prognostic marker in different shock states and other critical conditions [2-5]. Serum

lactate concentrations > 4 mmol/L are unusual in normal and not critically ill hospitalized

patients, independent of underlying comorbidities [6]. Lactate concentration > 4 mmol/L in the

presence of systemic inflammatory response syndrome (SIRS) criteria significantly increases

intensive care unit (ICU) admission rates and mortality rate in normotensive patients [7].

Also, lactate represents a useful and clinically obtainable surrogate marker of tissue hypoxia

and disease severity, independent of blood pressure [8]. This was corroborated by others,

who also demonstrated that early lactate clearance was associated with decreased mortality

rate in patients with severe sepsis and post-cardiac arrest patients [9,10]. These findings

have facilitated the clinical application of point-of-care measurements and portable

monitoring of lactate over the past decade in the emergency department (ED), operating

theatre and ICU [11-13]. In addition, several years ago Shapiro et al. suggested that lactate

seemed a promising risk-stratification tool in the ED setting [14]. They found a significant

higher mortality rate in patients with a serum lactate ≥ 4 mmol/L. Measurement of serum

lactate in a pre-hospital setting, i.e. in the ambulance, could warn paramedics of pending

organ failure despite normal global hemodynamic parameters. We evaluated the relationship

of lactate measured in a pre clinical setting to outcome. Simultaneously, we evaluated the

feasibility of implementing blood lactate measurement in a pre-hospital setting as part of a

quality improvement project.

Methods

Setting

We studied charts of ambulances that arrived at a non-academic medical centre

[Gelre Hospital (GH), site Lukas, Apeldoorn, The Netherlands]. These charts are

standardized by the Dutch ambulance organization. The GH is an affiliated 925-bed teaching

hospital and the ICU is a 14-bed “closed format” department. The ambulance service covers

an area of about 2000 km2 with approximately 620,000 inhabitants. The ambulance service is

divided into 4 clusters, the main cluster being Apeldoorn, an urban area with approximately

270,000 inhabitants.

Implementation

From an environmental scan [15] we learned that in the Netherlands measurement of

lactate has not been done in daily practice throughout the pre-hospital phase. Because

lactate measurement was an unknown feature for our ambulance personnel the next phase

of implementation, setting a target, seemed important to prepare them for a change in

behaviour. To make behavioural change possible, teaching regarding why, what, and when

for changing behaviour is crucial. During the two months prior to the first blood lactate

measurements in pre-hospital setting all ambulance personnel was trained. First, as part of

the education program, one of the investigators (PS) explained in a lecture the theoretical

essence of this project. The why, the expected potential benefit for shock patients in the

future was also mentioned. Finally, all ambulance personnel received a two hour course on

working with the lactate meter (Accutrend© lactate meter (Roche Diagnostic GmbH) in the

field. This course was not only theoretical but also contained actual practice. With this course

we intended to lower the threshold in the field for the use of an extra device. The emphasis

on who to change was focused on the ambulance personnel.


This study is a chart review of patients from whom serum lactate levels prospectively

were obtained in a pre-hospital setting. Total population was divided into two groups, i.e. a

shock group and a non-shock group according to predefined shock symptoms which were

defined as 1) a heart rate <50 or >100 beats per minute, 2) systolic blood pressure <90

mmHg, 3) respiration rate <10 or >30 breaths per minute, 4) peripheral arterial oxygen

saturation <95% (COPD patients <90%), 5) collapse or Glasgow Coma Scale (GCS) <14.

Patients suffering from two or more of these symptoms were included in the shock group;

those with none or one deviated shock parameter were included in the control (non-shock)

group. Exclusion criteria were age <18 years, hypoglycemia, seizures, no consent, treatment

not according to the Dutch national ambulance protocol (“Landelijk Protocol Ambulance”,

LPA 7) or lacking data. In the field respiration rate was noted according to the Dutch national

ambulance chart, being five options: none, 1-5, 6-9, 10-29 and more than 30 breaths per

minute. For analysis, respiratory rates were divided into three categories: 0-9, 10-29 and >30

breaths per minute [16]. After defining the non-shock and shock group the latter population

was divided into two subgroups: one subgroup with blood lactate < 4 mmol/L (= subgroup I)

and another subgroup with blood lactate ≥ 4 mmol/L (= subgroup II). Early treatment given in

pre-hospital setting was divided in three categories: 1) oxygen plus basic peripheral IV line;

2) as previous, plus plasma expander; 3) as previous, plus intubation.

Lactate measurements

During the maintenance phase all lactate meters (Accutrend© lactate meter (Roche

Diagnostic GmbH) were calibrated regularly according instructions by the manufacturer.

Capillary or venous lactate levels were measured with these meters. Local coordinators were

interviewed on the experiences of the ambulance personnel, the lactate meter and its use in

the field. Also points for improvement were noted.

Vitals were determined with Lifepack© 12 (Medtronic). Collecting data was approved

by the Medical Ethics Committee. Informed consent was obtained from all participants.


The statistical package for the social sciences (SPSS 16.0.1 for Windows) was used

for statistical analysis. All data were tested for normal distribution with the Kolmogorov-

Smirnov test before further statistical analysis. Since normality could not be assumed,

differences between groups were assessed using non-parametric Mann-Witney U analysis

and Spearman correlation tests. Data were displayed as median and range. Categorical data

were tested by χ2 test. Receiver operating curves (ROC) curves were used to describe the

relation between increased lactate levels and vital signs and to evaluate their reliability as a

prognostic factor. In all cases a p-value < 0.05 was considered to be statistical significant.

Results

Implementation

In about 50% of possible cases lactate was measured in the pre-hospital setting in

the Apeldoorn area. The number of measurements was lower in more rural areas (24%).

Interviews with coordinators in the 4 clusters of the ambulance service revealed consistently

the same causes of non-compliance and the following barriers were encountered. Duration of

lactate measurement (60 seconds) resulted in restraint for a successive attempt. In the rural

areas especially, less frequent calls resulted in less experience in handling the lactate meter.

Measurement seemed less aggravating for ambulance personnel when for instance patients

hemodynamics were less deteriorated or when GCS was high or normal. Although personnel

were well aware of the possible reasons why to change medical acting in the field variation

from standard protocol (LPA 7) was still an issue. Overall, the majority of ambulance

personnel experienced inclusion criteria as too strict. An extra measurement was not always

considered possible in sometimes-stressful situations. On the other hand, occasional

feedback on particular cases such as repeated lactate measurements in the ED or ICU was

experienced as positive.

Lactate measurements

As a result of the implementation of lactate measurement in the pre-hospital setting a

total 277 ambulance charts were reviewed, allowing evaluation of clinical relevance. Sixty-

one charts did not meet inclusion criteria: forty-one patients were in pre-hospital setting

diagnosed with seizures, eighteen charts were invalid and two patients were not treated

according to the national ambulance protocol leaving 216 charts fit for study. Eighty-one

patients did not meet shock criteria (non-shock group) but 135 patients did (shock group).

Characteristics of the patients are shown in table 1.

The numbers of shock criteria per patient in the shock group were distributed as

follows: 2 criteria in 55 (40.8%) patients; 3 criteria in 41 (30.6%) patients; 4 criteria in 28

(20.4%) patients and 5 criteria in 11 (8.1%) patients. In normotensive shock patients (MAP

60-90mmHg) revealing a lactate ≥ 4mmol/L (n=27) the mortality was higher compared to

normotensive shock patients with a lactate < 4mmol/L (n=31) (35% vs. 7%; p < 0.001).

Median lactate in the shock group was significantly higher compared to the non-shock group:

3.9 (1.5-20.0) mmol/L vs. 2.8 (0.8-7.2) mmol/L (p < 0.0001). In hospital mortality differed

significantly from the non-shock group: 26.7% in the shock group vs. 1.2% in the control

group (p < 0.001).

In the shock subgroups (subgroup I: lactate < 4 mmol/L, n=74; subgroup II: lactate ≥ 4

mmol/L, n=61) age and sexes were equally distributed. Median lactate in subgroup I was 3.2

(1.5-3.9) mmol/L vs. 5.0 (4.0-20.0) mmol / L in subgroup II (p < 0.0001). Compared to

subgroup I more patients showed an unfavourable respiratory pattern in subgroup II

(category respiratory rate <10 or >29 breaths / minute) (35.1%vs. 65.6%). Only one patient

(1.4%) needed intubation in subgroup I but 15 patients (24.6%) needed intubation in

subgroup II (p < 0.001). Also significant differences were found in length of stay in intensive

care unit or critical care unit (LOSICU) (p = 0.03), length of hospital stay (LOSHOSP) (p = 0.04)

and mortality (subgroup I 12.2% vs. subgroup II 44.3%; p = 0.002). Results within the shock

group are shown in table 2.

Table 1. Base-line characteristics of non-shock and shock group.

non-shock group

(n=81)

shock group

(n=135)

P value

Age (yr)

Sex (%)

Male

Female

Heart rate (beats per minute)

Mean blood pressure (mmHg)

Respiratory rate

0-9

10-29

>29

Arterial saturation (%)

Lactate (mmol/L)

GCS

RTS

Diagnosis (%)

Trauma

Respiratory failure

Cardiac failure (incl. resuscitation)

Sepsis / infection

Haemorrhage

Acute abdomen

CNS

Other

LOSICU/CCU (days)

LOSHOSP (days)

In hospital mortality (%)

54 (18-94)

56.8

43.2

75 (51-146)

97 (61-133)

0

76

5

98 (84-100)

2.8 (0.8-7.2)

15 (6-15)

12 (10-12)

9.9

1.2

1.2

1.2

7.4

16.0

2.5

60.6

0 (0-1)

1 (0-26)

1.2

72 (18-91)

60.0

40.0

91 (0-150)

73 (0-140)

14

69

52

92 (0-100)

3.9 (1.5-20.0)

14 (3-15)

11 (0-12)

5.9

8.9

14.1

14.1

18.5

8.1

6.7

23.7

1 (0-46)

4 (0-53)

26.7

< 0.001*

0.67

0.005*

<0.0001*

0.004*

<0.0001*

<0.0001*

<0.0001*

<0.0001*

<0.0001*

<0.0001*

<0.0001*

Data presented as numbers or median (range). * Statistically significant difference. GCS, Glasgow Coma

Scale; RTS, Revised Trauma Score; CNS, central nervous system; LOSICU/CCU , length of stay in intensive or

critical care unit; LOSHOSP, length of stay in hospital.

Receiver operating characteristic (ROC) curves were constructed for measurements

taken in pre-hospital setting. These curves represent the reliability of different values as

predictors of in-hospital mortality. Area under the curve (AUC) was significantly higher for

lactate compared to vitals in both the total population (lactate 0.827 vs. SaO2 0.127, MAP

0.350 and heart rate 0.500; p < 0.01) and the shock group (lactate 0.775 vs. SaO2 0.157,

MAP 0.421 and heart rate 0.435; p < 0.01). We established a lactate level of 3.2mmol/L as

the best cut-off point. A lactate level of ≥ 3.2mmol/L was 75% sensitive (95% CI 62-88%) and

72% specific (62-82%) for prediction of death; figure 1.

Figure 1. ROC curves for mortality prediction in the

shock group. The AUC was 0.775 for lactate, 0.157 for

arterial saturation (SaO2), 0.421 for mean arterial

pressure (MAP) and 0.435 for heart rate (HR).

Table 2. Base-line characteristics subgroups of shock patients.

subgroup I (n=74)

(lactate < 4 mmol/L)

subgroup II (n=61)

(lactate ≥4 mmol/L)

p-value

Age (yr)

Sex (%)

Male

Female

Heart rate (beats per minute)

Mean blood pressure (mmHg)

Respiratory rate

0-9

10-29

>29

Arterial saturation (%)

Lactate (mmol/L)

GCS

RTS

Diagnosis (%)

Trauma

Respiratory failure

Cardiac failure (incl. resuscitation)

Sepsis / infection

Haemorrhage

Acute abdomen

CNS

Other

LOSICU/CCU (days)

LOSHOSP (days)

In hospital mortality (%)

74 (18-90)

56.8

43.2

82 (35-150)

78 (34-140)

3

48

23

94 (47-100)

3.2 (1.5-3.9)

15 (3-15)

11 (5-12)

4.1

12.2

9.5

10.8

14.9

10.8

6.8

30.9

0 (0-12)

1 (0-53)

12.2

70 (19-91)

63.9

36.1

99 (0-140)

70 (0-140)

11

21

29

88 (0-100)

5.0 (4.0-20.0)

15 (3-15)

10 (0-12)

8.2

4.9

19.7

18.0

23.0

4.9

6.6

14.7

1 (0-46)

7 (0-46)

44.3

0.59

0.40

0.20

0.77

0.01*

< 0.0001*

< 0.0001*

0.68

0.01*

0.07

0.03*

0.04*

0.02*

Data presented as numbers or median (range). * Statistically significant difference. GCS, Glasgow Coma

Scale; RTS, Revised Trauma Score; CNS, central nervous system; LOSICU/CCU , length of stay in intensive or

critical care unit; LOSHOSP, length of stay in hospital.

Discussion

Logistical implementation of lactate measurement on the ambulance services means

implementation of an extra medical act and extra effort. We concluded that this is feasible,

albeit difficult. One of the reasons for this difficulty is that we aimed at changing behaviour

without the presence of logistical or procedural errors that often motivate clinical collectives

to action [15]. Also, involving ED personnel, including consultants may enhance the chance

of success in a complex and dynamic environment such as the acute care that only can

function as result of interplay of diverse departments and teams [15,17]. Difficulty with lactate

measurements in very stressful situations or even ignoring such measurement during these

events seems reasonable. Lactate measurements are probably less important in patients

being resuscitated and in need for instant and maximum treatment. In these cases the

urgency is obvious and will be carried over to the ED personnel. However, during the

interviews it became clear that for the ambulance personnel lactate measurement in patients

with less deteriorated hemodynamics seemed less necessary. This is a pity, for lactate

measurement in the pre-hospital setting could especially be of use in this category of

patients: i.e. patients being more severely ill than could suspected by vitals only.

Consequently, a substantial number of patients with prognostically important hypoperfusion

remain undetected. Most importantly, high lactate levels should trigger for specific

intervention, i.e. fluid therapy, to improve lactate clearance and to improve outcome[18].

Treatment aiming at high lactate clearance is associated with decreased mortality rate in

severe sepsis patients with elevated baseline lactate but without hypotension [9]. Our results

seem concordant with the latter finding, i.e. mortality was significantly increased in

normotensive shock patients if their pre-hospital lactate level was ≥ 4mmol/L (7% vs. 35%).

Again, this finding is important because those patients would probably not be identified as

being critically ill in the pre-hospital or ED setting. Recently Howell et al. also found higher

mortality rates with increased lactate levels (≥4 mmol/L) in normotensive patients. In their

patient population with suspected infection they confirmed that a single lactate measurement

was independently predictive of mortality and not a surrogate marker of hypotension [19].

Early lactate determination seems helpful for triage decisions, not only in the ED, but also

before ED presentation. Patients might indeed benefit from advanced activation of medical

staff in the destination hospital.

Several limitations to our observations should be mentioned. First, this quality

improvement project was not powered to yield conclusions pertaining to the obtained lactate

measurements. Nevertheless, the data are interesting, since even in this small study strong

association between lactate and increased morbidity and mortality could be demonstrated.

This illustrates the importance of measuring lactate in the pre-hospital setting. Still, lactate

measurements were not compared with the lactate levels in the ED. Consequently, the

influence of lactate clearance could not be described and the use of the threshold value of

3.2mmol/L may therefore be of limited value. Second, lactate was measured either from

venous or capillary blood. Lactate determination in an ED or ICU can be done form venous

or arterial blood sample and in most previous studies on lactate measurements were done

arterially. In pre-hospital setting this is however not possible and venous (capillary) samples

are the first choice. Previous studies showed these measurements to be equivalent [20,21].

Finally, the lactate measurements are predominantly performed in the Apeldoorn area and

thus reflect a single centre observation. Further studies should reveal whether successful

implementation in several ambulance regions may yield comparable results and if lactate

measurements in the pre-hospital setting could be used as guideline for treatment.

We conclude that implementation of lactate measurement in pre-hospital setting is

feasible, albeit difficult and potentially clinical relevant. Subsequent studies should evaluate if

treatment based on pre-hospital lactate measurement will improve outcome.

Acknowledgements

The authors would like to thank Tjerk Loopik for his invaluable help in the acquisition

of patient data.

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lactate as a predictor of mortality in emergency department patients with infection.

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Chapter 6

Cumulative lactate in ICU patients: magnitude

matters

Paul van Beest, Lukas Brander,

Sebastiaan Jansen, Hans Rommes,

Michaël Kuiper, Peter Spronk

Abstract

Objective To evaluate whether lactate levels and derived variables are associated with

organ failure and in-hospital mortality in a mixed intensive care unit (ICU) population.

Methods Retrospective observational study. Case records from 2251 consecutive ICU

patients admitted between 2001 and 2007 were analyzed. Base line characteristics, all

lactate measurements, Sequential Organ Failure Assessment (SOFA) scores and in-hospital

mortality were recorded. The time integral of arterial blood lactate levels above the upper

normal threshold of 2.2 mmol/L (lactate-time-integral), maximum lactate (max-lactate), and

time-to-first-normalization, were calculated. Survivors and non-survivors were compared and

receiver operating characteristic (ROC) analysis were applied.

Results A total of 20755 serum lactate measurements were analyzed. In non-survivors

(n=405) lactate-time-integral, time-to-normal and cumulative SOFA were higher than in

hospital survivors (all p<0.001). AUC of ROC curves to predict in-hospital mortality was the

largest for max-lactate, whereas it was not different among all other lactate derived variables

(all p>0.05). The area under the ROC curves for admission lactate and lactate-time-integral

was not different (p=0.36).

Conclusion Cumulative lactate is associated with in-hospital mortality in a heterogeneous

ICU population. In our patients lactate peak values, but not the time integral of arterial blood

lactate levels above the upper normal threshold predicted in-hospital mortality.

Introduction

Hyperlactataemia is common in critically ill patients and may reflect an imbalance

between local or systemic oxygen supply (DO2) and oxygen consumption (VO2).

Hyperlactataemia may also be found during increased aerobic glycolysis in hypermetabolic

states from various causes [1,2], in patients treated with catecholamines [3,4], as a

consequence of alkalosis in hyperventilation [5], and with impaired hepatic lactate clearance

in sepsis or low flow states [6]. Elevated serum lactate levels are associated with the

development of multiple organ dysfunction (MODS) postoperatively, following trauma, and

septic shock [7-10] and it has been suggested that hyperlactataemia is associated with

worse outcome [10-13]. Persistence of lactate levels above normal is associated with higher

mortality rates in patients with severe sepsis, septic shock [9,14] and in post-cardiac arrest

patients [15]. We hypothesized that the duration of hyperlactataemia represented by the time

integral of arterial blood lactate levels above the upper normal threshold of 2.2 mmol/L

(lactate-time-integral) outperforms single lactate measurements in predicting outcome.

We therefore retrospectively investigated the relationship between lactate derived

variables (admission level, maximum level, time-to first-normalization, lactate-time-integral)

and organ failure, as assessed by the Sequential Organ Failure Assessment (SOFA) score

[16-18], as well as in-hospital mortality in a large, mixed ICU population. Additionally, we

performed subgroup analysis on categories in which lactate has been described as predictor

of mortality (sepsis and circulatory failure) [10-13].

Methods

Setting

A retrospective observational study in a university affiliated teaching hospital where

the ICU is a mixed, 10 bed “closed format” department. There were no changes in medical

staff during the study period. Case records from all ICU patients with available serum lactate

measurements admitted over a 5-year period, January 2002 - December 2006, were

identified in the ICU database. The study was approved by the Local Ethics Committee that

waived the need for informed consent.

Data collection

Data from all days spent in the ICU were collected retrospectively from the electronic

patient data monitoring system and the hospital administration database. We collected

demographic information, diagnosis, acute physiology and chronic health evaluation

(APACHE II), simplified acute physiology score (SAPS-II), all serum lactate levels, and

relevant variables for calculation of daily-assessed SOFA score (table 1). Diagnosis

classifications were based on the APACHE II classifications, hence diagnosis category

weight [19]. Finally, length of stay in the ICU (ICULOS), days in the hospital before discharge

(LOSHOSP) and hospital survival were recorded.

Parameters of organ failure

SOFA scores were prospectively calculated daily during ICU stay on a routine basis.

The highest value for each organ system in the preceding 24-hour period was used. If

variables required for calculation were missing, they were considered as normal until the first

measured value became available. For any missing value thereafter, the last measured value

known was used. The following SOFA-derived variables were used:

1. Initial SOFA score on the first day of ICU admission (from time of admission to 24

hours following admission, e.g., from 6 am to 6 am the next day).

2. Cumulative SOFA (cum-SOFA): the sum of all daily SOFA scores during the stay in

the ICU.

If the patient received renal placement therapy (RRT) the maximum of 4 points was used for

the renal component of the SOFA score.

Lactate levels and derived variables

Lactate levels were measured in arterial blood using point-of-care blood gas

analyzers (Rapidlab 865, Siemens, Munich, Germany; upper normal limit 2.2mmol/L).

The time integral for lactate levels above the upper normal threshold of 2.2 mmol/L was

calculated during the entire ICU-stay (lactate-time-integral) using custom made software. We

used a formula that, for practical reasons, assumed a linear change over time between

measurements. Figure 1 illustrates four possible scenarios used for calculating lactate-time-

integral. Lactate buffer solutions for RRT and continuous epinephrine infusion were not used

during the study period following the general policy in the unit.


The statistical package for the social sciences (SPSS 16.0.1 for Windows, Chicago,

IL, USA) was used for statistical analyses and additional software was used for graphics

(Prism 5.0 for windows, La Jolla, CA, USA) and comparison of ROC curves (MedCalc 11.2.1,

Mariakerke, Belgium). Data are presented as mean ± SD or

Figure 1. Illustration on calculation of lactate area under the curve above the

upper normal limit of serum lactate (2.2 mmol/L). The following four equations

were used in computing lactate-AUC:

1. AUC A = ((½ · (lactate 0 – lactate 1)) + lactate 1)) · (time 1 – time 0)

2. AUC B = ((½ · (lactate 2 – lactate 1)) + lactate 1)) · (time 2 – time 1)

3. AUC C = ((lactate 2 – 2.2)² · (time 3 – time 2)) / 2 · lactate 2

4. AUC D = ((lactate 4 – 2.2)² · (time 4 – time 3)) / 2 · lactate 4

median [inter-quartile range] as indicated by assessment of normal distribution (D’Agostino-

Pearson omnibus normality test). Wilcoxon rank-sum test was used for categorical data.

Differences of admission source or admission diagnosis between groups of survivors and

non-survivors and those with and without hyperlactataemia were assessed using the Chi

square test. Receiver Operating Characteristic (ROC) curves were used for the assessment

of sensitivity and specificity of lactate derived variables in predicting in-hospital mortality.

Areas under the ROC curves (AUCROC) were compared by the method described by DeLong

et al. [20]. Statistical significance was assumed at p < 0.05.

Results

Table 1. Baseline and clinical characteristics

characteristics all

n = 2251

surv

n = 1846

non surv

n = 405

P value a

age (yr) 66 (12-98) 69 (57-76) 75 (67-81)

sex M : F (%) 61 : 39 61 : 39 60 : 40

SAPS-II 38 (20-113) 33 (24-43) 51 (41-65) < 0.001 *

APACHE II 17 (10-54) 15 (11-19) 23 (17-28) < 0.001 *

diagnosis (%)

vasc surg

abd surg

other surg

heart failure

resp failure

GI bleeding

neurological

other

sepsis

16.0

22.4

9.8

14.8

11.8

3.8

4.5

3.7

13.1

17.2

23.5

10.9

12.3

11.5

4.3

4.6

3.9

11.8

10.4

17.2

4.9

26.4

13.4

1.5

2.7

4.2

19.2

< 0.01 # *

vasoactive agent (%) 33 28 57 < 0.001 *

LOS ICU (days) 2 (1-5) 2 (1-5) 3 (1-8) < 0.001 *

LOS HOSP (days) 14 (7-27) 15 (9-28) 6 (2-16) < 0.001 *

in hosp mortality (%) 18

Data are presented as numbers and median (interquartile range). AUC, area under the curve; surv,

survivors; non surv, non-survivors; SAPS-II, simplified acute physiology score; APACHE II, acute

physiology, age and chronic health evaluation; vasc surg, vascular surgery; abd surg, abdominal

surgery; resp failure, respiratory failure; GI, gastrointestinal; vasoactive agent: noradrenaline,

dopamine, dobutamine, phosphodeisterase inhibitor; LOS ICU, length of stay at intensive care;

LOS HOSP, length of stay at hospital; in hosp mortality, in-hospital mortality; a survivors vs. non-

survivors, * Statistically significant difference. Statistics by Chi-square tests

# and Wilcoxon rank-

sum tests.

During the 5-year period case records of 2251 patients (age 66 [12-98] years; 39%

female) were identified. A total of 20755 serum lactate measurements were analyzed.

Median lactate concentration at admission was 1.7 [1.1-2.8] mmol/L; minimum 0.6 mmol/L

and maximum 27.0 mmol/L. Max-lactate was 2.1 [1.5-3.3] mmol/L, and lactate-time-integral

0.0 [0.0-244] min·mmol/L. Baseline and clinical characteristics of all patients are summarized

in table 1 (total population) and table 2 (subgroups).

Table 2. Baseline characteristics subgroups

characteristic sepsis

n=307

respiratory failure

n=303

cardiac failure

n=213

trauma

n=76

hemorrhage

n=165

age (yr) 69 (60-77) 68 (57-76) 72 (63-78) 37 (24-66) 70 (58-78)

sex M : F (%) 63 : 37 58 : 42 60 : 40 75 : 25 61 : 38

SAPS II 48 (37-57) 39 (31-50) 48 (37-63) 24 (17-35) 36 (28-45)

APACHE II 21 (17-26) 18 (14-22) 22 (16-28) 11 (8-16) 15 (11-19)

heart rate (beats/min) 115 (96-130) 115 (95-130) 110 (80-125) 95 (80-110) 100 (85-115)

syst BP (mmHg) 105 (80-130) 123 (105-140) 110 (85-140) 123 (105-140) 105 (85-135)

MAP (mmHg) 58 (50-62) 63 (55-69) 59 (51-65) 65 (58-74) 62 (55-70)

vasoactive agent (%) 56 36 56 20 31

mech. ventilation (%) 49 47 63 59 36

lactate (mmol/L) 2.4 (1.6-3.9) 1.7 (1.1-2.6) 2.4 (1.4-4.8) 2.0 (1.4-3.2) 1.0 (0-2.1)

max lactate (mmol/L) 3.0 (2.1-4.9) 2.1 (1.6-2.9) 3.0 (1.9-5.2) 2.3 (1.5-3.3) 1.2 (0-2.8)

cum-lactate

(min·mmol/L)

216 (0-2634) 0 (0-143) 138 (0-1245) 1 (0-243) 0 (0-38)

in hosp mortality (%) 29 21 38 8 8

Data are presented as numbers and median (interquartile range). SAPS-II, simplified acute physiology score; APACHE II,

acute physiology, age and chronic health evaluation

In-hospital mortality of our population was 18% and was higher in patients with

hyperlactataemia during ICU-stay compared to those without hyperlactataemia (26.4% vs.

10.8%; p < 0.001; table 1). In patients who died in the hospital (n = 405), admission lactate

(2.6 [1.5-5.0] mmol/L), max-lactate (3.2 [1.9-5.8] mmol/L) and lactate-time-integral (192 [0-

1881] min·mmol/L), were higher than in hospital survivors (n = 1846; admission lactate (1.6

[1.1-2.5] mmol/L), max-lactate (2.0 [1.4-3.0] mmol/L) and lactate-time-integral 0 [0-134]

min·mmol/L, respectively; all p < 0.001); Figure 2.

p < 0.001


1

10

ad

mis

sio

n lacta

te

(mm

ol / L

)

p < 0.001


1

2

4

8

16

max. la

cta

te

(mm

ol/L

)

p < 0.01


1

2

4

8

16

cu

m S

OFA

/ d

ay

(po

ints

/ d

ay)

p < 0.001


1

10

100

1000

10000

lacta

te-t

ime

-in

teg

ral / d

ay

([m

in

mm

ol

/ L

] /

da

y)

Figure 2. Admission lactate levels (mmol/L), maximum lactate levels (mmol/L), cum-SOFA

per day (points/day), lactate-time-integral per day ([min·mmol/L]/day) for survivors (n =

1846) and non-survivors (n = 405); bars show median (upper interquartile range);

logarithmic scale.

Figure 3 illustrates the relationship between lactate-time-integral per day and cum-

SOFA per day in survivors (n=1846) and non-survivors (n=405). Geometric means [95% CI]

of lactate-time-integral per day ([min·mmol/L] / day) and of cum-SOFA per day (points / day)

were significantly higher in non-survivors (174 [128-236] min·mmol/L / day and 11.1 [10.5-

11.8] points / day) compared to survivors (44 [40-51] min·mmol/L / day and 9.1 [8.9-9.4]

points / day); both p < 0.001.

1 10 100 1000 100005

8

13

20

survivors (n = 1846)

nonsurvivors (n = 405)

cum-lactate per day ( [min mmol / L] / day )

cum

-SO

FA

per

day

(p

oin

ts /

day

)

Figure 3. Relationship between lactate-time-integral per day and cum-SOFA per day

in both survivors and non-survivors: geometric means (open dot: survivors, closed

dot: non-survivors) with 95% confidence intervals; logarithmic scale.

Figure 4 demonstrates the difference between admission lactate levels and lactate-

derived variables with respect to predicting in-hospital mortality. AUCROC for admission

lactate and lactate-time-integral were similar (0.666 [95% CI 0.646 to 0.686] vs. 0.676 [95%

CI 0.657 to 0.696]; p=0.36). AUCROC for max-lactate (0.692 [95% CI 0.672 to 0.711]) was

larger than AUCROC for lactate (0.666 [95% CI 0.646 to 0.686]; p = 0.01) lactate-time-integral

(0.676 [95% CI 0.657 to 0.696]; p < 0.01), and time to normal (0.552 [95% CI 0.531 to

0.573]; p < 0.001). The cut-off points derived from the ROC curve for lactate, max-lactate

and cumulative lactate were 2.7 mmol/L, 2.5 mmol/L and 53 min·mmol/L, respectively.

Fig. 4 Receiver operating characteristic curves for in-hospital

mortality prediction. Area under the curve was 0.552 for time to

normal, 0.666 for lactate, 0.676 for lactate-time-integral and 0.692

maximum lactate

Subgroup analysis revealed similar results. In none of the subgroups (sepsis, n=307;

cardiac failure, n=213) AUCROC for lactate-time-integral was larger than AUCROC for single

lactate values. In all subgroups admission lactate and maximum lactate differed between

survivors and non survivors (all p < 0.001).

Discussion

In the present study lactate-time-integral was not superior in predicting in-hospital

mortality compared to admission or maximum arterial lactate concentrations. Admission

lactate values, maximum lactate values during ICU stay, and lactate-time-integral, were all

associated with in-hospital mortality.

High lactate clearance within the first 6 hours of sepsis is associated with decreased

60-day mortality, even in the absence of arterial hypotension: survivors compared with non-

survivors had a lactate clearance of 38 vs. 12%, respectively [14]. Recently, in a randomized

study, the use of lactate clearance was described as an efficacious alternative for ScvO2

(target > 70%) guided resuscitation of patients in septic shock [21]. However, due to practical

reasons a treatment bias could not be excluded. Also, difference in protocol actions were

small: despite a well performed study chance may have influenced the results. In the present

study we did not look at lactate clearance as described by Nguyen et al, a ratio of lactate

values, but a combination of the lactate derived variables used may be considered as a

surrogate. Yet, in the subgroup of patients with sepsis the lactate-time-integral or time to

normal did not outperform max-lactate. This was the case in a study in which the duration of

hyperlactataemia, lactime, was the best discriminant of survival when the patients who died

in the first 24 hours were excluded [10]. We performed a retrospective study and choose not

to exclude those patients who died early after onset of the disease to picture the influence of

lactate and lactate derived variables in clinical reality. In conclusion, the present results

recognize the importance of lactate clearance as described by others but also underline the

importance of magnitude of lactate values during ICU treatment.

A serum lactate threshold of ≥ 4 mmol/L has been used to initiate protocol-based

resuscitation [22,23]. Such an approach might imply acceptance of intermediate serum

lactate levels in the range of 2 to 4 mmol/L. However, elevated mortality rates are also

described in critically ill patients with only moderate elevated serum lactate levels during or

even before admission to the emergency department (ED) [24-26]. Additionally, in two recent

retrospective studies the relationship between lactate levels, lactate derived variables and

outcome in critically ill patients was assessed. It was concluded that not only

hyperlactataemia but also relative hyperlactataemia, i.e. lactate levels in the upper normal

range, are associated with increased mortality [27,28]. Our results in ICU patients are

concordant with these results and we believe that normal values provide a reasonable

clinical sign that tissue oxygenation is adequate and the metabolism is primarily aerobic.

Nevertheless, it is possible that a higher lactate concentration threshold would have revealed

different results. In addition, our results suggest that presence of hyperlactataemia

outperforms its persistence in predicting in-hospital mortality. This might also be explained by

two other factors. First, the retrospective design of our study and the lack of a specific

intervention protocol limits the generalisation of our results. Second, arterial lactate

concentrations not only depend on lactate production but also on its clearance. It is not

known whether one mechanism is more important than the other with respect to outcome

prediction. Nevertheless, the mechanism causing hyperlactataemia may play an important

role in outcome prediction, rather than the hyperlactataemia itself. For instance, as described

in two recent reports [30,31], the severity of hyperlactataemia due to metformin accumulation

alone does not predict outcome but even in those cases the causative role is uncertain. Also,

co morbidities such as renal insufficiency of liver failure may play an additional role [30,31].

Finally, non-survivors revealed shorter LOSICU and LOSHOSP, whereas lactate-time-

integral was significantly higher in non-survivors compared to survivors. This means that

non-survivors accumulate enough SOFA points to predict outcome independent of LOSICU as

illustrated in figure 3. The duration and magnitude of increased serum lactate levels,

represented by the area under the lactate curve, is associated with final outcome.

Nevertheless, in the present study the specificity and sensitivity, described by AUCROC, of

admission lactate and lactate-time-integral were similar in predicting in-hospital mortality.

Several limitations to our observations should be considered. First, this was a

retrospective study, which precludes definitive conclusions. On top of that, there was no

predefined lactate measurement or lactate-based goal-directed protocol. However, we

consider the results strong enough to warrant further prospective studies analyzing the

described phenomena, particularly, because the data were collected over a 5 year period

and derived from a large group of patients. Second, this was a single unit study and therefore

the results may only reflect the regional population and ICU management strategies.

Nevertheless, we believe that selection bias was minimized since all consecutive admissions

were included in the data analysis, since there was no change in medical staffing, and

admission and discharge criteria were stable during the study period. Third, we assumed a

linear change in time between two lactate measurements, which is a simplification of a real

biologic process. However, we believe that our approach represents an approximation with

acceptable precision for the purpose of the present study.

We conclude that lactate load correlated with cumulative SOFA score and is

associated with in-hospital mortality in a heterogeneous ICU population. Additionally,

magnitude of serum lactate levels and not necessarily duration of elevated serum lactate

levels are of value in predicting in-hospital mortality.

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Chapter 7

Veno-arterial PCO2 difference as a tool in

resuscitation of septic patients

Paul van Beest, Mariska Lont, Nicole Holman,

Bert Loef, Michaël Kuiper,

Christiaan Boerma

Abstract

Purpose To investigate the interchangeability of mixed and central venous-to-arterial carbon

dioxide differences and the relation between the central venous-to-arterial carbon dioxide

differences (pCO2 gap) and cardiac index (CI). We also investigated the value of the pCO2

gap in outcome prediction.

Methods We performed a post-hoc analysis of a well-defined population of 53 patients with

severe sepsis or septic shock. Mixed and central venous pCO2 were determined earlier at a

6-hour interval (T=0 to T=4) during the first 24 hours after intensive care unit (ICU)

admittance. The population was divided into two groups based on pCO2 gap (cut off value

0.8 kPa).

Results The mixed pCO2 difference underestimated the central pCO2 difference by a mean

bias of 0.03 kPa ± 0.32 kPa ( 95% limits of agreement: -0.62 kPa to 0.58 kPa). We observed

a weak relation between pCO2 gap and CI. The in hospital mortality rate was 21% (6/29) for

low gap group and 29% (7/24) for high gap group; Odds ratio 1.6 (95% CI 0.5-5.5), p = 0.53.

At T=4 the Odds ratio was 5.3 (95% CI 0.9-30.7); p=0.08.

Conclusions The central venous pCO2 should not be used as surrogate for the mixed

venous pCO2 in patients with severe sepsis or septic shock. The likelihood of bad outcome

enhances when a high pCO2 gap persists after 24 hours of therapy.

Introduction


systemic oxygen delivery (DO2) and oxygen demand (VO2). Global tissue hypoxia as a result

of systemic inflammatory response or circulatory failure is an important indicator of serious

illness preceding multiple organ failure. The development of organ failure predicts outcome

of the septic patient [1]. Unrecognized and untreated global tissue hypoxia increases

morbidity and mortality: decreased mixed venous oxygen saturation (SvO2) values or central

venous oxygen saturation (ScvO2) values predict poor prognosis in septic shock [2,3].

However, in the majority of patients with severe sepsis or septic shock who are acutely

admitted to the intensive care unit (ICU) ScvO2 values are >70% [4,5]. Hence, normal ScvO2

values do not guarantee adequate tissue oxygenation and other circulatory parameters are

needed to evaluate resuscitation efforts.

A variable that has been described in this context is the central venous-to-arterial

carbon dioxide difference (pCO2 gap) [6]. Under physiological conditions, venous-to-arterial

carbon dioxide difference usually does not exceed 0.8 kPa (6 mmHg) [7] and reflects

adequacy of venous blood flow, i.e. cardiac output (CO) [8,9]. On macro-circulatory level, an

inverse relationship between pCO2 gap and cardiac index (CI) has been described in

critically ill patients [10,11]. Indeed, in patients who fulfilled resuscitation endpoints according

to international guidelines [1] a cutoff value for pCO2 gap of 0.8 kPa discriminated between

high and low lactate clearance and CI [6]. Thus, combining ScvO2 values as surrogate for

global tissue hypoxia and pCO2 gap as surrogate for CI may be useful during resuscitation of

critically ill patients. However in patients with severe sepsis, on the microcirculatory level

distributive changes may be independent of CO [12,13]. This means that, on a regional level,

in accordance to the possibility of persistent tissue hypoxia despite normal ScvO2 levels,

accumulation of carbon dioxide (CO2) may occur in sepsis despite adequate CO.

In line with investigations on the agreement between SvO2 and ScvO2, it seems

useful to determine whether an agreement between mixed and central venous-to-arterial

carbon dioxide difference in septic patients exists [5,11]. In other words, are mixed and

central venous-to-arterial carbon dioxide difference interchangeable?

We examined the relationship between central venous-to-arterial carbon dioxide

difference and CI and we addressed the question whether central venous-to-arterial carbon

dioxide differences are of additional value in outcome prediction. Additionally, we

investigated the agreement between mixed and central venous-to-arterial carbon dioxide

difference in a well defined population of patients with severe sepsis or septic shock [5].

Methods

Setting

We studied ICU populations in two teaching hospitals: the Martini Hospital

[Groningen, The Netherlands] (MH) with a 14-bed “closed format” mixed medical / surgical

ICU department and the Medical Center Leeuwarden [Leeuwarden, The Netherlands] (MCL)

with a 16-bed “closed format” mixed medical / surgical ICU, including cardiothoracic patients.

Previously, written informed consent was obtained in all cases from the patient or from the

patient’s legal representative. The use of earlier obtained data [5] was approved by both

Local Ethics Committees.


This post-hoc analysis of data from a prospective observational study included a

population of patients we have described before [5]. All patients were 18 years or older, with

sepsis or septic shock according to international criteria as the principal reason for ICU

admittance [14]. Patients were included in case of a clinical indication for additional

hemodynamic monitoring using a pulmonary artery catheter (PAC) [Criticath SP 5507H TD,

Becton Dickinson, Singapore] or a Continuous Cardiac Output (CCO) catheter [Arrow

Deutschland GmbH, Erding, Germany]. The catheter was inserted into an internal jugular or

subclavian vein according to standard procedure. Position was confirmed by the presence of

pulmonary artery pressure tracings and chest radiography. Primary data, including

hemodynamic variables, were collected at 6-hour interval (T0, T1, T2, T3, T4) during the first

24 hours after acute ICU admittance. Standard blood samples of 2 ml were drawn

simultaneously from arterial line, distal (pulmonary artery; PA) and proximal / side portal

(superior caval vein; SCV) from PAC or CCO catheter. To avoid falsely high readings due to

aspiration of pulmonary capillary blood, aspiration was done gently to avoid high negative

pressure when blood samples were taken. Blood was sampled from the proximal port of the

catheter as representative of central venous blood [15,16]. All blood samples were analyzed

by a point-of-care co-oximeter (Radiometer ABL800 flex, Copenhagen, Denmark) available

in both ICU’s. The Acute Physiology, Age and Chronic Health Evaluation (APACHE) II-score

after 24 hours of ICU admittance was calculated [17].


For analysis the population was divided into two groups: patients with a low pCO2 gap

(<0.8kPa) vs. patients with a high pCO2 gap (>0.8kPa) at ICU admission (T=0). Statistical

tests were two-tailed and performed by the statistical package for the social sciences (IBM

SPSS 19 for Windows, Chicago, IL, USA) or MedCalc software (version 11.2.1, Mariakerke,

Belgium) for comparing ROC curves. GraphPad software (Prism 5.0, La Jolla, CA, USA) was

used for graphics. Measurements were not independent but clustered within each patient. All

data were tested for normal distribution with the D’Agostino-Pearson omnibus normality test

before further statistical analysis. Differences between both groups were assessed using

Student’s t-test in case of normal distribution. For categorical data Chi-Square test or

Fisher’s exact test was used. For each time point (T0-T4) the difference between arterial CO2

partial pressure (paCO2) and central venous (pvCO2), i.e. pCO2 gap was calculated. Also, for

each time point the average of CI, mean arterial pressure (MAP), ScvO2, lactate, and infusion

rate of both norepinephrine and dopamine was calculated. The agreement between CI and

pCO2 gap was assessed by the mean bias and 95% limits of agreement (mean bias ± 1.96 x

standard deviation) as described by Bland and Altman (BA) [18]. Pearson correlation

coefficient between mixed and central venous pCO2 differences was determined. Finally, the

odds ratio for mortality between patients with a high pCO2 gap and patients with a low pCO2

gap at both T=0 and T=4 was calculated. Data are displayed as mean ± SD. Statistical

significance was assumed at p < 0.05.

Results

We enrolled 56 patients, of whom three patients were excluded due to lack of data

(technical problems). We evaluated data from 53 patients with sepsis. Thirty patients were

enrolled at MCL and 23 patients were enrolled at MH. No complications other than transient

arrhythmias were observed during the insertion of any catheter.

Altogether 245 paired blood samples were obtained. At T=0, 29 patients had a central

pCO2 difference less than 0.8 kPa (low gap group), and 24 patients had a central pCO2

difference larger than 0.8 kPa (high gap group). Baseline characteristics and outcome of the

total population and both groups are shown in table 1. Length of stay at the ICU (LOS ICU) was

12 ± 10 days and length of stay at the hospital (LOSHOSP) was 25 ± 18 days.

Table 1. Baseline characteristics

variable total population (n=53) low gap (n=29) high gap (n=24) P value #

age (yr) 66 ± 12 67 ± 13 66 ± 11 0.83

gender (m/f) 28 / 25 17 / 12 11 / 13 0.41 1)

APACHE II 27 ± 8 26 ± 7 27 ± 9 0.70

diagnosis 0.78 1)

abdominal 25 13 9

respiratory 16 10 7

urological 5 2 3

other 7 4 5

therapy

mechanical ventilation 52 / 53 28 / 29 24 / 24 1.00 2)

RRT 15 / 53 5 / 29 10 / 24 0.08 2)

dopamine (µg/kg/min) 4.1 ± 3.9 3.6 ± 3.5 4.8 ± 2.7 0.41

norepinephrine (µg/kg/min) 0.20 ± 0.18 0.23 ± 0.23 0.16 ± 0.19 0.35

MAP (mmHg) 66 ± 10 68 ± 9 63 ± 11 0.11

CVP (mmHg) 12 ± 6 12 ± 5 13 ± 6 0.38

CI (L/min/m2) 3.7 ± 1.2 4.1 ± 1.1 3.3 ± 1.1 0.01

*

lactate (mmol/L) 3.3± 3.0 2.8 ± 3.1 3.9 ± 2.9 0.19

ScvO2 (%) 71.8 ± 10.1 74.5 ± 9.3 71.1 ± 7.1 < 0.001 *

SvO2 (%) 71.9 ± 10.7 73.2 ± 9.1 70.3 ± 6.6 < 0.01 *

pCO2 difference (kPa) 0.70 ± 0.52 0.38 ± 0.42 1.10 ± 0.33 < 0.001 *

hematocrit (%) 31 ± 1 30 ± 5 31 ± 6 0.49

SaO2 (%) 96 ± 2 97 ± 2 96 ± 3 0.37

pH 7.30 ± 0.10 7.31 ± 0.09 7.29 ± 0.11 0.59

Data are presented as mean ± SD or as numbers; # low gap vs. high gap group; APACHE II, acute physiology, age

and chronic health evaluation; RRT, renal replacement therapy; MAP, mean arterial pressure; CVP, central venous

pressure; CI, cardiac index; ScvO2, central venous oxygen saturation; SvO2, mixed venous oxygen saturation;

SaO2, arterial oxygen saturation; 1) Fisher’s exact test;

2) Chi Square test;

* statistically significant difference

Agreement mixed and central pCO2 difference

The mixed pCO2 difference underestimated the central pCO2 difference by a mean

bias (or absolute difference) of 0.03 ± 0.32 kPa in all paired measurements. The 95% limits

of agreement ranged from -0.62 to 0.58 kPa (figure 1). Correlation was significant (p < 0.001)

with Pearson correlation coefficient r of 0.57. Mean delta was not significantly different from 0

(p = 0.11): both values tend to be equal. This was confirmed by an intra-class coefficient

between the mixed and central pCO2 differences of 0.70 (p < 0.001).

T=0

-2 0 2-2

-1

0

1

2

(PmvCO2 + PcvCO2) / 2

Pm

vC

O2 -

Pc

vC

O2 (

kP

a)

Figure 1. Bland and Altman plots showing the agreement between mixed

venous pCO2 (PmvCO2) and central venous pCO2 (PcvCO2) at T=0.

Mean bias 0.03 ± 0.32 kPa; 95% limits of agreement from -0.62 to 0.58

kPa.

The results at various time points were similar with at T=0 a mean bias of -0.13 ± 0.40

kPa and 95% limits of agreement of -1.0 to 0.8 kPa.

When the central pCO2 difference was plotted against CI for all paired measurements,

there was an inverse logarithmic relationship with increasing central pCO2 difference as CI

decreased (regression equation: CO2gap = 10 (-0.90 CI + 0.07) ; R2 = 0.07 p < 0.0001; figure 2).

0 2 4 6 8 100

1

2

3

CI (L/min/m2)

CO

2 g

ap

(k

Pa)

Figure 2. Correlation between central venous pCO2 difference and

cardiac index in total population for all paired measurements at T=0. R2

= 0.07; p < 0.0001.

Differences between low gap and high gap group

At T=0, low gap group patients had a significantly lower pCO2 gap than patients of the

high gap group (0.38 ± 0.42 kPa vs. 1.10 ± 0.33 kPa; p < 0.001). There was no significant

difference between the two groups for age, gender, APACHE II, diagnosis and treatment

received (table 1). The groups did not differ in both arterial blood pressure with equivalent

inotropic doses and degree of hyperlactaemia. CI was significantly lower in the high gap

group (3.3 ± 1.1 L/min/m2 vs. 4.1 ± 1.1 L/min/m2; p = 0.01).

Figure 3 shows the evolution in time of the central pCO2 difference and CI. During the

first 24 hours of treatment there was no significant difference in ScvO2 (except for T=0),

MAP, and lactate. At all time points, there was no significant difference in either

norepinephrine and dopamine infusion rate or the number of patients receiving these

catecholamines.

0.0

0.5

1.0

1.5high gap low gap

0 1 2 3 4

# #

timepoints

PC

O2 d

iffe

ren

ce

(k

Pa

)

2.5

3.0

3.5

4.0

4.5high gap low gap

0 1 2 3 4

# #

timepoints

ca

rdia

c in

de

x (

L/m

in/m

2)

Figure 3. Evolution in time of central pCO2 difference and

cardiac index for both high gap and low gap group; time

interval between time points: 6 hours. #, statistically

significant difference.

Outcome

The hospital mortality rate for all patients was 24.5% (13/53). The in hospital mortality

rate was 21% (6/29) for low gap group and 29% (7/24) for high gap group; Odds ratio 1.6

(95% CI 0.5-5.5), p = 0.53. Patients with a central pCO2 difference larger than 0.8kPa at T=4

had a higher mortality change (n=8; in hospital mortality 38%) compared to patients with a

central pCO2 difference smaller than 0.8kPa at T=4 (n=39; in hospital mortality 10%): Odds

ratio 5.3 (95% CI 0.9-30.7); p=0.08.

Discussion

We observed a strong agreement between the mixed venous pCO2 and the central

venous pCO2 differences with seemingly relatively small limits of agreement in patients with

severe sepsis or septic shock. From a practical perspective, the clinical utility of central pCO2

values is of potential interest in determining the venous-arterial pCO2 difference. The present

BA analysis implacably demonstrates a strong agreement between mixed and central

venous pCO2 differences. This in line with recent findings by Cuschieri et al. who described

a mixed population of critically ill patients, including patients with circulatory and cardiogenic

shock. They observed a minimal but significant difference with slightly higher mean mixed

pCO2 values compared to mean central pCO2 values (difference 0.02kPa) [11]. Similarly, we

found a mean delta equal to zero. Despite the practical attractiveness of the abovementioned

observations, we believe that the 95% limits of agreement (-0.62 to 0.58 kPa; and -1.0 to 0.8

kPa at T=0) are relatively wide compared to the clinical relevant cutoff value of 0.8 kPa. This

means that both central venous pCO2 values as well as mixed venous pCO2 values may be

used for the calculation of a venous-arterial pCO2 difference, but that clinicians should not

interchange these variables during treatment.

We observed a weak but significant inverse logarithmic relation between the pCO2

gap and global blood flow, i.e. CI, in this specific sepsis population. Indeed, this is in line with

physiological theory, which describes an inverse curvilineair relation between cardiac output

and pCO2 difference, according to a modified Fick equation for a range of CO2-production-

isopleths [19]. Various studies described such an inverse relationship between mixed

venous-arterial pCO2 difference and CI in septic circulatory failure [20-22]. The increase in

the venous-arterial pCO2 gradient is explained by a inadequate washout of CO2. Hence, a

low-flow state is characterized by failure in oxygen delivery to the tissues and excesses of

CO2 in venous blood. In addition to this, in sepsis an increase in pCO2 difference may persist

in higher ranges of cardiac output. Due to heterogeneity of microcirculatory blood flow,

inadequate washout of CO2 in microcirculatory weakunits, despite normal of even elevated

cardiac output, has been observed during sepsis [12,13]. Vallée et al. [6] tested this

hypothesis in patients with septic shock, who were supposedly adequately resuscitated at

the systemic level, with a ScvO2 ≥ 70% [1]. A central venous-arterial pCO2 difference > 6

mmHg at baseline was inversely correlated with lactate clearance and reduction in SOFA

score after 24 hours. This might be due to the observed significant lower cardiac index in the

high gap group, but the normal ScvO2 also points towards the possibility of distributive

deficits of a normal or elevated systemic blood flow. As expected [4], in our population the

mean ScvO2 values were higher than 70%. The far majority the patients with a high CO2 gap

at ICU admittance were in the horizontal part of the cardiac output - CO2 gap curve, indicating

the relative independence of the two variables in this particular range of systemic blood flow.

Finally, the predictive value of the pCO2 difference for outcome is questionable.

However, a modest time-dependent relationship between an increased pCO2 difference and

outcome was found. Although not significant, with the persistence of an increased pCO2

difference the Odds ratio for bad outcome increases. Whether the significantly higher CI and

ScvO2 in the low pCO2-gap group is causatively related or an epiphenomenon remains topic

of debate, since protocols that aim for supranormal values have been proven to be harmful in

critically ill patients [23,24].

This study has limitations. First, this is a multicenter, post-hoc study, and its

observational character has clear limitations. Second, statements about any impact on

therapeutic intervention are not possible. Third, since all patients were septic, our findings

may not be generalized to patients less critically ill or to those with other forms of shock.

Finally, lack of clear insight of treatment prior to ICU admittance at the different EDs or wards

is a limitation of our study as well. Nevertheless, since we aimed at the usefulness of the

central venous CO2 difference after ICU admittance, we think these factors are not pertinent

to the results.

Conclusion

Both central venous pCO2 values as well as mixed venous pCO2 values may be used

for the calculation of a venous-arterial pCO2 difference, but they should not be

interchangeably during treatment of patients with severe sepsis or septic shock.

The central venous pCO2 difference correlates with CI but should not be used to

estimate CI in patients with severe sepsis and septic shock.

A priori, the predictive value for outcome of the central venous pCO2 difference is

questionable but persistence of an increased central venous pCO2 difference after 24 hours

of therapy enhances the likelihood of bad outcome.

References.


Keh D, Marshall J, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM. for


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1993, 103: 900-906.

3. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Tomlanovich M; Early

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fluids. In: Guyton AC (ed) Textbook of medical physiology, 10th edn. WB Saunders Co,

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8. Johnson BA, Weil MH: Redefining ischemia due to circulatory failure as dual defects

of oxygen deficits and of carbon dioxide excesses. Crit Care Med 1991, 19: 1432-

1438.

9. Weil MH, Rackow EC, Trevino R, Grundler W, Falk JL, Griffel MI: Difference in acid-

based state between venous and arterial blood during cardiopulmonary

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10. Durkin R, Gergits MA, Reed JF, Fitzgibbons J: The relationship between arteriovenous

carbon dioxide gradient and cardiac index. J Crit Care 1993, 8: 217-221.

11. Cuschieri J, Rivers EP, Donnino MW, Katilius M, Jacobson G, Nguyen HB, Pamukov N,

Horst HM: Central venous-arterial carbon dioxide difference as an indicator of

cardiac index. Intensive Care Med 2005, 31: 818-822.

12. Creteur J, De Backer D, Sakr Y, Koch M, Vincent JL: Sublingual capnometry tracks

microcirculatory changes in septic patients. Intensive Care Med 2006, 32: 516-523.

13. Fries M, Weil MH, Sun S, Huang L, Fang X, Cammarata G, Castillo C, Tang W: Increases

in tissue PCO2 during circulatory shock reflect selective decreases in capillary

blood flow. Crit Care Med 2006, 34: 446-452.

14. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM,

Vincent JL, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis

Definitions Conference. Intensive Care Med 2003, 29: 530-538.

15. Chwala LS, Zia H, Guttierez G, Katz NM, Seneff MG, Shah M: Lack of equivalence





outcome in critically ill patients. Intensive Care Med 2008, 34: 1662-1668.




observations per individual. J Biopharm Stat 2007, 17: 571-582.

19. Lamia B, Monnet X, Teboul JL: Meaning of arterio-venous PCO2 difference in

circulatory shock. Minerva Anesthesiol 2006, 72: 597-604.

20. Mecher CE, Rackow EC, Astiz ME, Weil MH: Venous hypercarbia associated with

severe sepsis and systemic hypoperfusion. Crit Care Med 1990, 18: 585-589.

21. Bakker J, Vincent JL, Gris Ph, Leon M, Coffernils M, Kahn RJ: Veno-arterial carbon

dioxide gradient in human septic shock. Chest 1992, 101: 509-515.

22. Rackow EC, Astiz ME, Mecher CE, Weil MH: Increased venous-arterial carbon dioxide

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23. Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, Fumagalli R – SvO2

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patients. N Engl J Med 1995, 333: 1025-1032.


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1717-1722.

Chapter 8

Summary

The majority of patients described in the present thesis were admitted at the various

hospitals and ICUs with severe sepsis or septic shock. Sepsis is a syndrome characterized

by infection acompanied by a systemic inflammatory response syndrome (SIRS), i.e. a

generalized condition which affects the entire body. With increasing seriousness organs fail

and (relative) hypotension occurs. The complexity of the pathophysiology of sepsis demands

treatment strategies that covers much more than just the prescription of the right antibiotic to

eliminate the source, e.g. bacteria. One crucial part of therapy is hemodynamic optimization

of the patient. This is recognized by the international Surviving Sepsis Campaign by

embracing the EGDT strategy [1]. Indeed, one can argue on the implementation of a single

center strategy in international guidelines [2,3] but this discussion may never blur the notion

of the strategy itself. Of course, goal-oriented manipulation of cardiac preload, afterload and

contractility, including ScvO2 monitoring is a valuable strategy in a subset of patients. The

results presented in chapter 2 subscribe this: early identification of patients at risk for

cardiovascular collapse is important as illustrated by the high mortality rate (57%) in the

small subset of patients with an initial ScvO2 <50%. Hence, low ScvO2 values do exist early

after ICU admittance, but apparently its incidence is very low (chapter 2) which makes

generalized EGDT application a premature activity [2]. However, to ignore a valuable

strategy such as EGDT at this stage may be an unwise thing to do. EGDT implies early

recognition of the critically ill patient and enforces continuous reassessment of treatment [4]

which is probably one of the greatest gains in treating patients with severe sepsis or septic

shock over the last decade. This also implies that irrespective of proper EGDT treatment the

clinician should not rest on his or her laurels once several treatment goals have been

achieved.

When a clinician sets several treatment goals, he or she should be aware of the value

of each goal used. Thus, pursuing abstract numbers without comprehension of their

relevance should be avoided. It should also not be considered to assume that a ScvO2 value

of 70% automatically means a SvO2 value of 65% in patients with severe sepsis or septic

shock. As applies to the trends of both values, the agreement between both absolute values

is unacceptably wide which means that ScvO2 does not reliably predict SvO2 (chapter 3). The

difference is not a fixed 5% as stated in many text books and both values should not be

considered numerically equal. This is not only of academic importance [5] but also clinically

relevant [6]. If one abandons SvO2 and uses ScvO2 in the resuscitation of critically patients

one should be aware that also information on pulmonary artery pressures, cardiac filling

pressures, and cardiac output is disposed. Nevertheless, alternative less invasive

hemodynamic monitoring devices such as transoesophageal echocardiography, PiCCO, and

Flo Trac are available [7,8]. With the use of these devices PAC-related complications can be

avoided [9].

The abovementioned lack of agreement between ScvO2 and SvO2 values does not

exclude the clinical use of both values separately. In line with earlier work [10], ScvO2 values

in nonsurvivors fell more frequently below the cutoff value of 70% compared to survivors and

SvO2 values below 65% were more frequently found in nonsurvivors compared to survivors.

This suggests that after the first hours of resuscitation monitoring of venous oxygen

saturations could still be clinically relevant.

When a central venous access via the jugular or subclavian vein is impossible a

relatively easy and safe option is central venous access via the femoral vein. The femoral

central venous line is an adequate route for administration of e.g. antibiotics or

catecholamines, although the risk for infectious and thrombotic complications should be kept

in mind [11]. However, it is not an adequate site to obtain data as a surrogate for ScvO2

values (chapter 4): SfvO2 cannot replace ScvO2. This is not only the case during surgery or

resuscitation of critically ill patients, including patients with septic shock, but also in stable

conditions. Thus ease, or incompetence, should never be a surrogate for good data.

Hopefully the data are convincing enough to abandon such practice in the future.

Treatment of shock implies improvement of the circulatory state with redistribution of

flow. Illustratively, four cases are mentioned in chapter 4 in which SfvO2 decreased after six

hours of treatment while ScvO2 increased. Three out of these four patients died. Although not

sufficiently powered, this underlines the urgency of shock treatment and the possible

consequences when a patient does not respond to treatment.

Before treatment, (septic) shock should be recognized as early as possible. Delayed

identification of global tissue hypoxia increases morbidity and mortality. When paramedics

can recognize critically ill patients better, they will be able not only to start treatment early but

also to inform ED personnel so appropriate measures can be taken. Vital signs are not

always accurate enough to detect global tissue hypoxia. Lactate however, rarely transcends

4 mmol/L in not critically ill patients and lactate also seems a useful additional risk

stratification tool [14-16]. Fortunately, the implementation of prehospital lactate measurement

is feasible (chapter 5). Unfortunately, less deteriorated hemodynamics does not trigger the

average paramedic to obtain a lactate measurement. This makes the implementation difficult

and strenuous efforts are necessary to train personnel on the use of early lactate

measurement. The results presented in chapter 5 are in line with earlier findings [17] and

support the conclusion that early lactate determination is helpful in early triage decisions.

With the present results in mind should we abolish measurement of vital signs and ignore

clinical presentation? Absolutely not: one should take both vitals and a lactate into account.

In the setting of the ICU it is common practice to take a lactate measurement.

However, the frequency of measurement varies in clinical practice. Especially during the first

hours of treatment regular measurements seem useful as part of reassessment. Indeed,

increased clearance during the first six resuscitation hours means better survival [18]. But

does the value of lactate evaporate after the first hours of ICU admittance? No: on-going

watchfulness is the order. Despite equivalent specificities and sensitivities for predicting in-

hospital mortality, not only lactate at admission but also lactate-derived variables were

significantly different between survivors and nonsurvivors (chapter 6). In addition,

persistence of hyperlactataemia was associated with organ failure expressed in (cumulative)

SOFA points. This provides a link to clinical practice and subscribes the use of lactate as a

risk-stratification tool [16].

How sensitive is lactate as a warning signal for organ failure and outcome? This

partly depends on the cut off point. The choice in chapter 6 for the threshold of 2.2 mmol/L

(upper normal limit) was a deliberate one. First, the goal is to ‘normalize’ the patients’ status

and second, also moderate elevated lactate levels decrease survival chances [1,17,19].

Another issue in this context is the mechanism causing hyperlactataemia which is probably

more important than the hyperlactataemia itself [20-22]. Hence, the question on predictive

sensitivity is difficult to answer and maybe not important. Of note, presence of

hyperlactataemia in ICU patients is important and should encourage the clinician to

reflection. To put the hyperlactataemia in perspective, the clinical picture, hemodynamics,

ScvO2, and vital signs should be considered.

During treatment of critically ill patients and the regular reassessment of this

treatment ScvO2 and lactate are useful but not perfect tools. The pCO2 gap described in

chapter 7 may indeed be a welcome additional application. This variable indirectly estimates

systemic blood flow and may help to identify the patients who remain inadequately

resuscitated [23]. When the pCO2 gap is used in clinical practice central venous and mixed

venous pCO2 values should not be used interchangeably for calculation of venous-arterial

pCO2 difference: although the 95% limits of agreement seem attractively small, they are

relatively wide (chapter 7).

A high pCO2 gap (> 0.8 kPa or > 6 mmHg) at ICU admission may be indicative for low

lactate clearance and limited reduction in SOFA score after 24 hours of treatment [23]. On

top of that, when the pCO2 gap remains high after 24 hours of treatment survival chances

seem to diminish (chapter 7). However, these results do not warrant the use of pCO2

difference in future treatment algorithms.

Taken together, the following conclusions can be derived from the studies described

in this thesis:

o The incidence of low ScvO2 values of acutely admitted critically ill patients is low in

Dutch ICUs. This is especially true for patients with sepsis or septic shock.

o In our setting, use of ScvO2-guided resuscitation may only be helpful in a small

subset of sepsis.

o Mean SvO2 values and mean ScvO2 values in acutely admitted critically ill patients,

including patients with severe sepsis or septic shock, are in the normal range in our

ICUs.

o ScvO2 does not reliably predict SvO2 in patients with sepsis, independent of sepsis

origin.

o The change of ScvO2 compared to the change of SvO2 is not more reliable than the

exact numerical values in patients with sepsis.

o SfvO2 cannot replace ScvO2, neither in stable conditions nor during surgery or during

the resuscitation phase in critically ill patients.

o The implementation of lactate measurement in pre-hospital setting is feasible and

potentially clinical relevant, albeit difficult. Subsequent studies should evaluate if

treatment based on pre-hospital lactate measurement will improve outcome.

o Persistence of hyperlactataemia is associated with organ failure expressed in

(cumulative) SOFA points.

o Lactate load is associated with in-hospital mortality in a heterogeneous ICU

population.

o The central venous pCO2 should not be used as surrogate for the mixed venous

pCO2 in patients with severe sepsis or septic shock.

o A priori, the predictive value for outcome of the central venous pCO2 difference is

questionable but persistence of an increased central venous pCO2 difference after 24

hours of therapy seem to enhance the likelihood of bad outcome in patients with

severe sepsis or septic shock.

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2. Bellomo R, Reade MC, Warrillow SJ: The pursuit of high central venous oxygen


3. Perel A: Bench-to-bedside review: The initial hemodynamic resuscitation of the septic

patient according to Surviving Sepsis Campaign guidelines - does one size fit all?

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15. Bernardin G, Pradier C, Tiger F, Deloffre P, Mattei M: Blood pressure and arterial

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Nederlandse samenvatting

De meerderheid van de patiënten hier beschreven waren op de diverse intensive care

afdelingen (IC) opgenomen met ernstige sepsis of septische shock. Sepsis is een syndroom

wat voortkomt uit de reacties van het lichaam, inflammatoire respons, op een infectie; het

hele lichaam is hierbij betrokken. Bij toenemende ernst zullen organen minder goed gaan

functioneren zodat zelfs orgaanfalen ontstaat. Indien ook de bloeddruk in bepaalde mate

daalt wordt gesproken van septische shock. Vanwege de complexiteit van dit ziektebeeld

vereist de behandeling veel meer dan alleen het voorschrijven en toedienen van een

antibioticum. Zoals in internationale richtlijnen wordt beschreven, is het optimaliseren van de

hemodynamiek belangrijk onderdeel van de behandeling. Deze aanbeveling is gebaseerd op

één, overigens veelbetekende, strategie welke in één ziekenhuis werd uitgevoerd. Men kan

zich inderdaad de vraag stellen of de letterlijke implementatie van deze strategie in

internationale richtlijnen gewenst is. De resultaten waren indrukwekkend maar de resultaten

zijn ook nooit meer in gelijke mate elders behaald. Dit neemt niet weg dat de strategie om

doelgericht en op geleide van onder andere de centraal veneuze saturatie (ScvO2) de

cardiale ‘prestatie indicatoren’ (preload, afterload, contractiliteit) te verbeteren (‘Early Goal-

Directed Therapy’, EGDT) wel degelijk een waardevolle strategie is. De resultaten

beschreven in hoofdstuk 2 bevestigen dit: 57% van de patiënten met een zeer lage ScvO2

(<50%; normaal waarde 70%) bij opname overleeft de sepsis niet. Dus vroege herkenning

van de ernstig zieke patiënt met een hoog risico op hemodynamische ineenstorting

belangrijk zodat daarna tijdens de eerste uren ‘agressief’ behandeld kan worden.

Desalniettemin komen op Nederlandse IC’s bij acute opnames van septische patiënten zeer

weinig lage ScvO2 waarden voor (hoofdstuk 2). Algemene introductie van EGDT lijkt dus

voorbarig en zullen de resultaten van diverse grote studies verspreid over meerdere centra

EGDT in perspectief plaatsen. Hiermee wordt niet geïmpliceerd dat EDGT genegeerd moet

worden, in tegendeel. De arts wordt indachtig EGDT gedwongen de behandeling continue te

evalueren: op zijn of haar lauweren rusten is er niet bij! Deze geprotocolleerde aanpak is een

belangrijke vooruitgang in de behandeling van patiënten met ernstige sepsis of septische

shock.

Wanneer een arts bepaalde behandelingsdoelen nastreeft (bijvoorbeeld normalisatie

van de SvO2) dient hij of zij zich ook bewust te zijn van de waarde van elk doel. Met andere

woorden, het zonder enig begrip najagen van abstracte getallen (biologische parameters)

moet worden vermeden. Zo is het eveneens onverstandig bij septische patiënten aan te

nemen dat een normale ScvO2 (70%) automatisch een normale gemengd veneuze saturatie

(SvO2) betekent. Beide parameters zijn fysiologisch met elkaar verbonden maar zowel de

absolute waarden als de trend van beide parameters variëren te veel zodat ScvO2 de SvO2

niet betrouwbaar inschat (hoofdstuk 3). Dit is niet alleen van enig academisch belang maar is

ook klinisch relevant. Het vervangen van SvO2 waarden door ScvO2 waarden impliceert dat

de Swan Ganz katheter (arteria pulmonalis katheter; SG) waarmee de SvO2 wordt gemeten

in de kast blijft liggen. Hiermee worden de aan SG gerelateerde complicaties uiteraard

vermeden, maar tegelijkertijd wordt aanvullende informatie (arteria pulmonalis drukken,

cardiale vullings drukken, slagvolume) over boord gegooid.

Hoewel ScvO2 en SvO2 niet elkaars gelijke zijn, kunnen beide parameters nog steeds

onafhankelijk van elkaar gebruikt worden. Gedurende de eerste 24 uur na IC opname

werden meer lage ScvO2 en SvO2 waarden gezien bij patiënten die uiteindelijk in het

ziekenhuis overleden (nonsurvivors) dan bij patiënten die niet overleden (survivors). Dit

suggereert dat bepaling van veneuze saturaties ook ná de eerste uren relevant kan zijn.

Voor het bepalen van ScvO2 of SvO2 is een centraal veneuze toegang via de vena

jugularis interna of vena subclavia nodig. Wanneer het verkrijgen van een dergelijke toegang

niet lukt gecontra-indiceerd is er nog altijd een andere optie: de vena femoralis. Via deze

route kunnen ook catecholaminen en antibiotica worden toegediend, waarbij wel het risico

op mogelijke complicaties (infectie, thrombose) in het achterhoofd moet worden gehouden.

Echter, voor het vergaren van data als surrogaat voor ScvO2 is deze route ongeschikt: de

femoraal veneuze saturatie (SfvO2) is geen alternatief voor ScvO2 (hoofdstuk 4). Dit geldt

niet alleen bij kritisch zieke patiënten of patiënten die een operatie ondergaan maar zelfs ook

in de poliklinische setting (hoofdstuk 4). Hopelijk zijn de data gepresenteerd in hoofdstuk 4

overtuigend genoeg om dergelijke praktijken voortaan achterwege te laten. Gemak, of zelfs

incompetentie, mogen nooit leiden tot onbetrouwbare parameters.

Voordat een behandeling van ernstige sepsis of septische shock gestart kan worden

moet de patiënt met een dergelijk syndroom eerst worden herkend, en liefst zo snel mogelijk.

Vertraagde herkenning van weefsel hypoxie (globaal zuurstof tekort) leidt tot verhoogde

morbiditeit en sterfte. Als de ziekte al door paramedici, zoals ambulance personeel, herkend

kan worden is dat dus winst: de behandeling wordt snel gestart en het personeel op de

Spoedeisende Hulp (SEH) kan op de komst van een kritisch zieke patiënt worden

voorbereid. Conventionele parameters (bloeddruk, saturatie, hartslagfrequentie) zijn niet

altijd accuraat genoeg voor detectie van weefsel hypoxie. Buiten het ziekenhuis worden geen

centrale lijnen aangelegd en ScvO2 kan hier dus niet gebruikt worden als surrogaat voor

weefsel hypoxie. Lactaat lijkt een goed alternatief: lactaat is bij niet-kritisch zieke patiënten

zelden hoger dan 4 mmol/L en lactaat is al beschreven als hulpmiddel om risico op sterfte in

te schatten op een SEH. Gelukkig is de implementatie van een lactaat bepaling door

ambulance personeel haalbaar (hoofdstuk 5). Helaas voelt het ambulance personeel zich

echter niet altijd genegen bij patiënten met nog redelijke conventionele parameters het

lactaat ook daadwerkelijk af te nemen. Dat is jammer, want juist deze patiënten populatie

zou gebaat kunnen zijn bij vroege herkenning en behandeling van ziekte. Bovendien verloopt

de implementatie van lactaat meting in een pre-hospitale setting hierdoor moeizaam.

Overigens zijn de resultaten beschreven in hoofdstuk 5 geen vrijbrief om de conventionele

parameters en klinische presentatie van de patiënt te negeren: lactaat kan een belangrijk

hulpmiddel zijn.

Op de IC wordt regelmatig lactaat bepaald. Als onderdeel van een

behandelingsstrategie om het lactaat binnen 6 uur te normaliseren heeft lactaat zijn reeds

bewezen. Maar verdampt het nut na de eerste 6 uur? Dit lijkt het niet het geval en continue

alertheid is het devies want niet alleen het lactaat bij opname is van belang maar ook hogere

lactaat waarden gedurende het hele verblijf op de IC onderscheiden survivors van

nonsurvivors (hoofdstuk 7). Bovendien is een verhoogd lactaat geassocieerd met orgaan

falen uitgedrukt in SOFA score, het eerste teken aan de wand van verslechtering. Hierbij

moet wel worden opgemerkt dat uiteraard niet alleen naar een verhoogd lactaat

(hyperlactatemie) moet worden gekeken, maar dat dit ook in perspectief moet worden

geplaatst.

Uit voorgaande blijkt dat zowel ScvO2 als lactaat nuttige parameters zijn tijdens de

behandeling van kritisch zieke patiënten. Echter, zo is ook gebleken, beide parameters zijn

niet perfect. In hoofdstuk 7 wordt nog een derde handvat aangereikt: het arterio-veneuze

pCO2 verschil (pCO2 gap). Met behulp van de pCO2 gap kan een inschatting worden

gemaakt van de circulatie (lees: bloed flow, slagvolume): een verhoogde pCO2 gap verraadt

een verlaagd slagvolume. Bovendien kan ook de pCO2 gap worden gebruikt om nog

onvoldoende behandelde, maar niet als dusdanig herkende patiënten worden herkend. Voor

de berekening kunnen zowel de centraal veneuze als gemengd veneuze pCO2 worden

gebruikt, maar beide getallen mogen niet met elkaar worden verwisseld. Met andere

woorden: ze zijn niet elkaars gelijke (hoofdstuk 7). Wanneer een verhoogde pCO2 gap na 24

uur behandeling op de IC verhoogd blijft dan daalt mogelijk de overlevingskans van de

patiënt: de shock kon niet adequaat genoeg worden bestreden.

Uit de hier beschreven studies kunnen de volgende conclusies worden getrokken:

o Lage ScvO2 waarden komen bij acuut opgenomen septische patiënten weinig voor.

o Resuscitatie op geleide van ScvO2 lijkt vooral waardevol in een klein deel patiënten

met ernstige sepsis.

o ‘Gemiddelde’ SvO2 en ScvO2 waarden bij acuut opgenomen septische patiënten zijn

normaal in Nederlandse IC’s.

o ScvO2 is geen betrouwbaar surrogaat voor SvO2 bij septische patiënten; dit geldt niet

alleen voor de absolute getallen maar ook voor de veranderingen.

o SfvO2 mag niet gebruikt worden als surrogaat voor ScvO2 bij zowel stabiele cardiale

poliklinische patiënten, patiënten die chirurgie ondergaan of bij kritisch zieke

patiënten.

o Het implementeren van lactaat metingen door ambulance personeel is mogelijk,

moeizaam maar waarschijnlijk wel klinisch relevant.

o Voortdurende hyperlactatemie is geassocieerd met orgaan falen, uitgedrukt in SOFA

score.

o Lactaat is geassocieerd met sterfte in een heterogene IC populatie.

o De centraal veneuze pCO2 is geen surrogaat voor de gemengd veneuze pCO2 bij

patiënten met ernstige sepsis of septische shock.

o A priori is de voorspellende waarde van het centraal veneuze pCO2 verschil (pCO2

gap) voor sterfte nihil, maar een persisterend verhoogde pCO2 gap na 24 uur

behandeling op de IC lijkt de kans op sterfte te verhogen bij patiënten met ernstige

sepsis of septische shock.

Abbreviations

AMC Amsterdam Medical Center

APACHE II acute physiology, age and chronic health evaluation

AUC area under the curve

CCO continuous cardiac output

CI cardiac index

CI confidence interval

CNS central nervous system

CO cardiac output

CO2 carbon dioxide

CPR cardiopulmonary resuscitation

CVC central venous catheter

CVP central venous pressure

DO2 systemic oxygen delivery

ED emergency department

EGDT early goal-directed therapy

GCS Glasgow Coma Scale

GDT goal-directed therapy

GH Gelre Hospital

Hct hematocrit

HR heart rate

ICU intensive care unit

LOA 95% limits of agreement

LPA Landelijk Protocol Ambulance

LOSHOSP length of hospital stay

LOSICU length of ICU stay

LOSICU / CCU length of intensive care unit / critical care unit stay

MAP mean arterial pressure

MCL Medical Center Leeuwarden

MH Martini Hospital

MODS multiple organ dysfunction syndrome

O2 oxygen

O2ER oxygen extraction ratio

PA pulmonary artery

PAC pulmonary artery catheter

PaCO2 arterial CO2 partial pressure

PCO2 gap central venous to arterial carbon dioxide difference

PvCO2 central venous CO2 partial pressure

ROC receiver operating characteristic

RRT renal replacement therapy

RTS revised trauma score

SAP systolic arterial pressure

SAPS simplified acute physiology score

SaO2 arterial oxygen saturation

SCV superior caval vein

ScvO2 central venous oxygen saturation

S(c)vO2 mixed / central venous oxygen saturation

(ScvO2 – SvO2) difference between ScvO2 and SvO2

SfvO2 femoral venous oxygen saturation

SIRS systemic inflammatory response syndrome

SOFA sequential organ failure assessment

SvO2 mixed venous oxygen saturation

VO2 systemic oxygen demand

Publications

(full papers)

Colpaert C, Vermeulen P, van Beest P, Jeuris W, Goovaerts G, Weyler J, Van Dam P, Dirix L, Van

Marck E: Early distant relapse in ‘node-negative’ breast cancer patients is not predicted by

occult axillary lymph node metastases, but the features of the primary tumor. J Pathol 2001,

193(4): 442-449.

Colpaert C, Vermeulen P, van Beest P, Goovaerts G, Weyler J, Van Dam P, Dirix L, Van Marck E:

Intratumoural hypoxia resulting in the presence of a fibrotic focus is an independent predictor

of early distant relapse in lymph node negative breast cancer patients. Histopathology 2001, 39:

416-425.

Colpaert C, Vermeulen P, Benoy I, Soubry A, Van Roy F, van Beest P, Goovaerts G, Dirix L, Van Dam

P, Fox S, Harris A, Van Marck E: Inflammatory breast cancer shows angiogenesis with high

endothelial proliferation rate and strong E-cadherin expression. Br J Cancer 2003, 88: 718-25.

Colpaert C, Vermeulen P, Lachaert R, van Beest P, Goovaerts G, Dirix L, Van Marck E: Cutaneous

breast cancer deposits show distinct growth patterns with different degrees of angiogenesis

and fibrin deposition. Histopathology 2003, 42: 530-540.

van Beest PA, Hofstra JJ, Schultz MJ, Boerma EC, Spronk P, Kuiper MA: The incidence of low

venous oxygen saturation on admission in the ICU: a multicenter observational study in the

Netherlands. Crit Care 2008, 12: R33

van Beest PA, Kuiper MA: Interpretatie van centraal of gemengd veneuze saturatie en rechter

ventrikel ejectie fractie op de intensive care. Congresboek Venticare 2009: 133-143.

van Beest PA, Mulder PJ, Bambang Oetomo S, van den Broek B, Kuiper MA, Spronk PE:

Measurement of lactate in a prehospital is related to outcome. Eur J Emerg Med 2009, 16 (6):

318-322.

van Beest PA, van Ingen J, Boerma EC, Holman ND, Groen H, Koopmans M, Spronk PE, Kuiper MA:

Relation between mixed venous and central venous saturation in sepsis: no influence of sepsis

origin. Crit Care 2010, 14: 219.

van Beest PA, Wietasch JKG, Scheeren TWL, Spronk PE, Kuiper MA: The use of venous oxygen

saturations as a goal: a yet unfinished puzzle. A clinical review. Crit Care 2011, 15: 232.

van Beest PA, Spronk PE: Vroegtijdige doelgerichte therapie; hoofdstuk 13; Handboek

Multiorgaanfalen, eerste druk 2012; red. Groeneveld ABJ, Schultz MJ, Vroom MB; uitgeverij De

Tijdstroom.

van Beest PA, van der Schors A, Liefers H, Coenen LGJ, Braam RL, Habib N, Braber A, Scheeren

TWL, Kuiper MA, Spronk PE: Femoral venous oxygen saturation is no surrogate for central

venous oxygen saturation. Crit Care Med 2012, accepted.

van Beest PA, Brander L, Jansen SPA, Rommes JH, Kuiper MA, Spronk PE: Cumulative lactate in

ICU patients: magnitude matters. 2012, submitted.

van Beest PA, Lont M, Holman N, Loef B, Kuiper MA, Boerma EC: Veno-arterial PCO2 difference as

a tool in resuscitation of septic patients: time matters. 2012, submitted.

Dankwoord

Dit proefschrift is het resultaat van een samenwerking met tien afdelingen binnen zeven

verschillende medische centra. Er zijn dan ook zeer velen aan wie ik veel dank verschuldigd

ben: u bent mij allen dierbaar. Zonder alle hulp was het simpelweg niet gelukt een dergelijk

project naast mijn opleiding tot anesthesioloog af te ronden. Het waren achtenzeventig

buitengewoon interessante maanden waarin tot mijn genoegen het nuttige ook met het

aangename kon worden verenigd: “Het moet wel leuk blijven!”

Staat u mij toe een aantal personen bij naam te noemen en hen te bedanken.

Dr. M.A. Kuiper, beste Michaël, ruim zes jaar geleden sprak jij mij aan over deelname aan

een onderzoek. Je had een idee en met groot enthousiasme stopte je me een copy in

handen; ik moest maar eens gaan lezen en nadenken. Dat heb ik gedaan. Sindsdien heb ik

je leren kennen als een zeer innemend mens en integer clinicus en vorser op wie een

uitspraak van Confucius wel van toepassing is: “twijfel is de waakhond van het inzicht.”

Popper had het kunnen zeggen, vind je ook niet? Naast wetenschap is muziek een primaire

levensbehoefte voor jou en na de uren jazzles op vinyl in jouw muziekkamer groeit ook mijn

collectie, op CD dat wel, gestaag: dat is genieten!

Dr. P.E. Spronk, beste Peter, via cyberspace kwam ik voor het eerst in aanraking met jou,

althans jouw werk, meer bepaald jouw commentaar op mijn wetenschappelijke gespartel.

Dat was even slikken: niet mals maar wel buitengewoon leerzaam. Na de kennismaking in

Brussel veranderde jouw commentaar niet maar mijn interpretatie wel. En dat is toch wel

kenmerkend: jouw motivatie en ongebreideld enthousiasme besprenkeld met een sausje van

humor werken aanstekelijk. Hoewel mijn hoofd menigmaal tolde van de nieuwe input na een

bezoekje Apeldoorn reed ik met goede moed weer naar huis in de hoop snel weer eens iets

“over de schutting te flikkeren”!

Professor dr. T.W.L. Scheeren, beste Thomas, ruim twee jaar geleden heb jij tot mijn

genoegen de taak van promotor aanvaard. In deze periode heb ik dankbaar gebruik gemaakt

van jouw kennis en kunde. Ik dank jou niet alleen voor de kritieken maar ook voor

interessante en vrolijke gesprekken. Gelukkig ziet het er naar uit dat onze wetenschappelijke

wegen zich voorlopig niet scheiden!

Dr. J.K.G. Wietasch, beste Götz, uit hoofde van jouw functie als opleider was je al snel

betrokken bij dit project. Je bleek veel meer dan een opleider en ik dank jou dan ook hartelijk

voor de logistieke en mentale ondersteuning. Daarnaast was je niet alleen een uiterst

betrouwbare gesprekspartner maar ook een zeer welkome tafelgast!

Graag neem ik van de gelegenheid gebruik om de leden van de beoordelingscommissie,

Prof. Dr. J. Bakker, Prof. Dr. W.F. Buhre en Prof. Dr. M.M.R.F. Struys te bedanken voor de

tijd en moeite welke zij zich getroost hebben om dit proefschrift te beoordelen.

Beste paranimfen, Remco en Dedmer, twee grote broers die mij in deze tijden bijstaan: beter

had ik mij niet kunnen wensen. Dank jullie wel!

Mijn ouders, Ineke en Henk, ben ik zeer veel verschuldigd. Mede dankzij het warme, stabiele

nest, alle steun en het onmetelijke geduld ben ik nu niet alleen wie ik ben, maar ook wat ik

ben, namelijk anesthesioloog en doctor in medische wetenschappen. Liefs en dank!

Muriël en Kim, Jocelyne en Dorian en Bastiaan: wat mooi en fijn dat jullie familie zijn!

Anne en Haydée, wat moet ik zonder de morele steun, adviezen en nuchterheid? Helemaal

niets. Liefs en dank!

Wandert en Laura: dank voor de lach en getoonde interesse! We moeten maar weer eens zo

snel mogelijk en zo lang mogelijk tafelen op ons dakterras.

Alle vrienden en vriendinnen: dank jullie wel, uit de grond van hart hoop ik dat jullie nog lang

vrienden en vriendinnen zullen zijn!

Lieve Amber, mijn liefste, vrolijke roerige tijden maken we mee en ondertussen moet ik zo

nodig iets wetenschappelijks doen…Gelukkig plaats jij alles met een olijke blik of een

nuchtere opmerking in perspectief. Ik dank je voor de vrolijke noot, het luisterend oor en

briljante ideetjes, en nog veel meer!

Lieve Bram, dankzij jou is alles zo heerlijk relatief. Je hebt nu nog geen idee en dat moet je

misschien maar zo lang mogelijk volhouden. Of doe stiekem net alsof.

university of groningen oxygen debt in critically ill patients beest, … · 2019. 11. 12. · 3....

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